EP1114028B1 - Aza-bicycles which modulate the inhibition of cell adhesion - Google Patents

Aza-bicycles which modulate the inhibition of cell adhesion Download PDF

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Publication number
EP1114028B1
EP1114028B1 EP99943058A EP99943058A EP1114028B1 EP 1114028 B1 EP1114028 B1 EP 1114028B1 EP 99943058 A EP99943058 A EP 99943058A EP 99943058 A EP99943058 A EP 99943058A EP 1114028 B1 EP1114028 B1 EP 1114028B1
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alkyl
group
compound according
aryl
hydrogen
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French (fr)
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EP1114028A1 (en
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Jean-Dominique Rhône-Poulenc Rorer R.D. BOURZAT
Alain Rhone-Poulenc Rorer Rech. Dev. COMMERCON
Bruno Jacques Christophe Rhone-Poulenc FILOCHE
Neil Victor Rhone-Poulenc Rorer Limited HARRIS
Clive Rhone-Poulenc Rorer Limited McCARTHY
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Sanofi Aventis UK Holdings Ltd
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Aventis Pharma Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/08—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms with acylated ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention is directed to aza-bicycles, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states capable of being modulated by the inhibition of cell adhesion.
  • Cell adhesion is a process by which cells associate with each other, migrate towards a specific target or localise within the extra-cellular matrix.
  • Many of the cell-cell and cell-extracellular matrix interactions are mediated by protein ligands (e.g. fibronectin, VCAM-1 and vitronectin) and their integrin receptors [e.g. ⁇ 5 ⁇ 1 (VLA-5), ⁇ 4 ⁇ 1 (VLA-4) and ⁇ V ⁇ 3].
  • protein ligands e.g. fibronectin, VCAM-1 and vitronectin
  • integrin receptors e.g. ⁇ 5 ⁇ 1 (VLA-5), ⁇ 4 ⁇ 1 (VLA-4) and ⁇ V ⁇ 3].
  • Recent studies have shown these interactions to play an important part in many physiological (e.g. embryonic development and wound healing) and pathological conditions (e.g. tumour-cell invasion and metastasis, inflammation, atherosclerosis and autoimmune disease).
  • proteins serve as ligands for integrin receptors.
  • the proteins recognised by integrins fall into one of three classes: extracellular matrix proteins, plasma proteins and cell surface proteins.
  • Extracellular matrix proteins such as collagen fibronectin, fibrinogen, laminin, thrombospondin and vitronectin bind to a number of integrins.
  • Many of the adhesive proteins also circulate in plasma and bind to activated blood cells. Additional components in plasma that are ligands for integrins include fibrinogen and factor X.
  • Ig-like cell adhesion molecule Ig-like cell adhesion molecule
  • VCAM-1 vascular cell adhesion molecule
  • Integrins are heterodimeric cell surface receptors consisting of two subunits called ⁇ and ⁇ . There are at least fifteen different ⁇ -subunits ( ⁇ 1- ⁇ 9, ⁇ -L, ⁇ -M, ⁇ -X, ⁇ -IIb, ⁇ -V and ⁇ -E) and at least seven different ⁇ ( ⁇ 1- ⁇ 7) subunits.
  • the integrin family can be subdivided into classes based on the ⁇ subunits, which can be associated with one or more ⁇ -subunits. The most widely distributed integrins belong to the ⁇ 1 class, also known as the very late antigens (VLA).
  • VLA very late antigens
  • the second class of integrins are leukocyte specific receptors and consist of one of three ⁇ -subunits ( ⁇ -L, ⁇ -M or ⁇ -X) complexed with the ⁇ 2 protein.
  • the present invention principally relates to agents which modulate the interaction of the ligand VCAM-1 with its integrin receptor ⁇ 4 ⁇ 1 (VLA-4), which is expressed on numerous hematopoietic cells and established cell lines, including hematopoietic precursors, peripheral and cytotoxic T lymphocytes, B lymphocytes, monocytes, thymocytes and eosinophils.
  • VLA-4 integrin receptor ⁇ 4 ⁇ 1
  • the integrin ⁇ 4 ⁇ 1 mediates both cell-cell and cell-matrix interactions.
  • Cells expressing ⁇ 4 ⁇ 1 bind to the carboxy-terminal cell binding domain (CS-1) of the extracellular matrix protein fibronectin, to the cytokine-inducible endothelial cell surface protein VCAM-1, and to each other to promote homotypic aggregation.
  • CS-1 carboxy-terminal cell binding domain
  • VCAM-1 cytokine-inducible endothelial cell surface protein
  • the expression of VCAM-1 by endothelial cells is upregulated by proinflammatory cytokines such as INF- ⁇ , TNF- ⁇ , IL-1 ⁇ and IL-4.
  • ⁇ 4 ⁇ 1 mediated cell adhesion is important in numerous physiological processes, including T-cell proliferation, B-cell localisation to germinal centres, and adhesion of activated T-cells and eosinophils to endothelial cells.
  • Evidence for the involvement of VLA-4/VCAM-1 interaction in various disease processes such as melanoma cell division in metastasis, T-cell infiltration of synovial membranes in rheumatoid arthritis, autoimmune diabetes, collitis and leukocyte penetration of the blood-brain barrier in experimental autoimmune encephalomyelitis, atherosclerosis, peripheral vascular disease, cardiovascular disease and multiple sclerosis, has been accumulated by investigating the role of the peptide CS-1 (the variable region of fibronectin to which ⁇ 4 ⁇ 1 binds via the sequence Leu-Asp-Val) and antibodies specific for VLA-4 or VCAM-1 in various in vitro and in vivo experimental models of inflammation.
  • peptide CS-1 the variable region of fibronectin
  • Bicyclic glycine derivatives of 7-aminodeacetoxycephalosporanic acid have been studied for use as orally adsorbable antibiotics (SJ Kukolja et al. J. Med. Chem., 1985,28, pages 1896-1903).
  • Anticancer compositions are described in WO 9807716, having receptor specificity as well as activity in simulating formation of the enzyme transglutaminase as a marker for anticancer activity.
  • the compositions comprise certain heteroarotinoid structures partially related to trans-retinoic acid through the basic, fused-ring framework.
  • Indole and indoline derivatives are disclosed in EP 0042298 for use in the treatment of diabetes mellitus, hyperlipoproteinaemic states of atherosclerosis, and of associated disorders. Tetrahydro-6-quinolineacetic acid derivatives have been shown to have antirheumatic activity and suppressive effect on bone destruction (Kohno, Yasushi et al. Bioorg. Med. Chem. Lett., 1997,7, pages 1519-1524).
  • the present invention is directed to aza-bicycles of general formula (I):- wherein:-
  • the term "compounds of the invention”, and equivalent expressions, are meant to embrace compounds of general formula (I) as hereinbefore described, which expression includes the ester prodrugs, protected derivatives of compounds of formula (I) containing one or more acidic functional groups and/or amino-acid side chains, the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, where the context so permits.
  • reference to intermediates, whether or not they themselves are claimed is meant to embrace their salts, and solvates, where the context so permits.
  • particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits.
  • Patient includes both human and other mammals.
  • Acid bioisostere means a group which has chemical and physical similarities producing broadly similar biological properties to a carboxy group (see Lipinski, Annual Reports in Medicinal Chemistry, 1986,21,p283 "Bioisosterism In Drug Design”; Yun, Hwahak Sekye, 1993,33,p576-579 "Application Of Bioisosterism To New Drug Design”; Zhao, Huaxue Tongbao, 1995,p34-38 "Bioisosteric Replacement And Development Of Lead Compounds In Drug Design”; Graham, Theochem, 1995,343,p105-109 "Theoretical Studies Applied To Drug Design:ab initio Electronic Distributions In Bioisosteres”).
  • Acidic functional group means a group with an acidic hydrogen within it.
  • the “protected derivatives” are those where the acidic hydrogen atom has been replaced with a suitable protecting group.
  • suitable protecting groups see T.W. Greene and P.G.M.Wuts in "Protective Groups in Organic Chemistry” John Wiley and Sons, 1991.
  • Exemplary acidic functional groups include carboxyl (and acid bioisosteres), hydroxy, mercapto and imidazole.
  • Exemplary protected derivatives include esters of carboxy groups (i.e. -CO 2 R 14 ), ethers of hydroxy groups (i.e. -OR 14 ), thioethers of mercapto groups (i.e. -SR 14 ), and N-benzyl derivatives of imidazoles.
  • Acyl means an H-CO- or alkyl-CO- group in which the alkyl group is as described herein.
  • acylamino is an acyl-NH- group wherein acyl is as defined herein.
  • Alkenyl means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear chain; here a linear alkenyl chain.
  • “Lower alkenyl” means about 2 to about 4 carbon atoms in the chain which may be straight or branched.
  • alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.
  • Alkenylene means an aliphatic bivalent radical derived from a straight or branched alkenyl group, in which the alkenyl group is as described herein.
  • alkenylene radicals include vinylene and propylene.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as described herein.
  • exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.
  • Alkoxycarbonyl means an alkyl-O-CO- group in which the alkyl group is as described herein.
  • exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.
  • Alkyl means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 15 carbon atoms in the chain. Particular alkyl groups have from 1 to about 6 carbon atoms.
  • “Lower alkyl” as a group or part of a lower alkoxy, lower alkylthio, lower alkylsulphinyl or lower alkylsulphonyl group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 4 carbon atoms in the chain.
  • Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl.
  • Alkylene means an aliphatic bivalent radical derived from a straight or branched C 1-6 alkyl group, in which the alkyl group is as described herein.
  • exemplary alkylene radicals include methylene, ethylene and trimethylene.
  • Alkylenedioxy means an -O-alkyl-O- group in which the alkyl group is as defined above.
  • exemplary alkylenedioxy groups include methylenedioxy and ethylenedioxy.
  • Alkylsulphinyl means an alkyl-SO- group in which the alkyl group is as previously described.
  • Preferred alkylsulphinyl groups are those in which the alkyl group is C 1-4 alkyl.
  • Alkylsulphonyl means an alkyl-SO 2 - group in which the alkyl group is as previously described.
  • Preferred alkylsulphonyl groups are those in which the alkyl group is C 1-4 alkyl.
  • Preferred alkylsulphonylcarbamoyl groups are those in which the alkyl group is C 1-4 alkyl.
  • Alkylthio means an alkyl-S- group in which the alkyl group is as previously described.
  • exemplary alkylthio groups include methylthio, ethylthio, isopropylthio and heptylthio.
  • Alkynyl means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, i-butynyl, 3-methylbut-2-ynyl, and n-pentynyl.
  • Alkynylene means an aliphatic bivalent radical derived from a C 2-6 alkynyl group.
  • exemplary alkynylene radicals include ethynylene and propynylene.
  • amino acid side chains means the substituent found on the carbon between the amino and carboxy groups in ⁇ -amino acids.
  • protected derivatives of amino acid side chains, see T.W. Greene and P.G.M.Wuts in "Protective Groups in Organic Chemistry” John Wiley and Sons, 1991.
  • Aroyl means an aryl-CO- group in which the aryl group is as described herein.
  • Exemplary aroyl groups include benzoyl and 1- and 2-naphthoyl.
  • Aroylamino is an aroyl-NH- group wherein aroyl is as previously defined.
  • Aryl as a group or part of a group denotes: (i) a monocyclic or multicyclic aromatic carbocyclic moiety of about 6 to about 14 carbon atoms, such as phenyl or naphthyl; or (ii) a partially saturated multicyclic aromatic carbocyclic moiety in which an aryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure, such as a tetrahydronaphthyl, indenyl or indanyl ring.
  • Aryl groups may be substituted with one or more aryl group substituents which may be the same or different, where "aryl group substituent" includes, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulphinyl, alkylsulphonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulphinyl, arylsulphonyl, arylthio, carboxy, cyano, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, hydroxy, nitro, trifluoromethyl, Y 1 Y 2 N-, Y 1 Y 2 NCO-, Y 1 Y 2 NSO 2 -
  • Arylalkenyl means an aryl-alkenyl- group in which the aryl and alkenyl are as previously described. Preferred arylalkenyls contain a lower alkenyl moiety. Exemplary arylalkenyl groups include styryl and phenylallyl.
  • Arylalkyl means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C 1-4 alkyl moiety. Exemplary arylalkyl groups include benzyl, 2-phenethyl and naphthlenemethyl.
  • Arylalkyloxy means an arylalkyl-O- group in which the arylalkyl groups is as previously described.
  • exemplary arylalkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
  • Arylalkyloxycarbonyl means an arylalkyl-O-CO- group in which the arylalkyl groups is as previously described.
  • An exemplary arylalkyloxycarbonyl group is benzyloxycarbonyl.
  • Arylalkylthio means an arylalkyl-S- group in which the arylalkyl group is as previously described.
  • An exemplary arylalkylthio group is benzylthio.
  • Arylalkynyl means an aryl-alkynyl- group in which the aryl and alkynyl are as previously described.
  • exemplary arylalkynyl groups include phenylethynyl and 3-phenylbut-2-ynyl.
  • Arylene means a bivalent radical derived from an aryl group.
  • exemplary arylene groups include phenylene, naphthylene and indanylene. When Ar 1 is arylene this may particularly represent a phenylene.
  • Aryloxy means an aryl-O- group in which the aryl group is as previously described.
  • exemplary aryloxy groups include phenoxy and naphthoxy.
  • exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
  • Arylsulphinyl means an aryl-SO- group in which the aryl group is as previously described.
  • Arylsulphonyl means an aryl-SO 2 - group in which the aryl group is as previously described.
  • Arylthio means an aryl-S- group in which the aryl group is as previously described.
  • exemplary arylthio groups include phenylthio and naphthylthio.
  • Azaheteroaryl means an aromatic carbocyclic moiety of about 5 to about 10 ring members in which one of the ring members is nitrogen and the other ring members are chosen from carbon, oxygen, sulphur, or nitrogen.
  • Examples of azaheteroaryl groups include pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, imidazolyl, and benzimidazolyl.
  • Azaheteroaryldiyl means a bivalent radical derived from a heteroaryl group.
  • Cyclic amine means a 3 to 8 membered monocyclic cycloalkyl ring system where one of the ring carbon atoms is replaced by nitrogen and which (i) may optionally contain an additional heteroatom selected from O, S or NY 3 (where Y 3 is hydrogen, alkyl, arylalkyl, and aryl) and (ii) may be fused to additional aryl or heteroaryl ring to form a bicyclic ring system.
  • Exemplary cyclic amines include pyrrolidine, piperidine, morpholine, piperazine, indoline and pyrindoline.
  • Cycloalkenyl means a non-aromatic monocyclic or multicyctic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms.
  • Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • Cycloalkenylalkyl means a cycloalkenyl-alkyl- group in which the cycloalkenyl and alkyl moieties are as previously described.
  • Exemplary cycloalkenylalkyl groups include cyclopentenylmethyl, cyclohexenylmethyl or cycloheptenylmethyl.
  • Cycloalkenylene means a bivalent radical derived from an unsaturated monocyclic hydrocarbon of about 3 to about 10 carbon atoms by removing a hydrogen atom from each of two different carbon atoms of the ring.
  • exemplary cycloalkenylene radicals include cyclopentenylene and cyclohexenylene.
  • Cycloalkyl means a saturated monocyclic or bicyclic ring system of about 3 to about 10 carbon atoms optionally substituted by oxo.
  • Exemplary monocyclic cycloalkyl rings include C 3-8 cycloalkyl rings such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Cydoalkylalkenyl means a cycloalkyl-alkenyl- group in which the cycloalkyl and alkenyl moieties are as previously described.
  • Exemplary monocyclic cycloalkylalkenyl groups include cyclopentylvinylene and cyclohexylvinylene.
  • Cycloalkylalkyl means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as previously described.
  • Exemplary monocyclic cycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
  • Cycloalkylalkynyl means a cycloalkyl-alkynyl- group in which the cycloalkyl and alkynyl moieties are as previously described.
  • Exemplary monocyclic cycloalkylalkynyl groups include cyclopropylethynyl, cyclopentylethynyl and cyclohexylethynyl.
  • Cycloalkylene means a bivalent radical derived from a saturated monocyclic hydrocarbon of about 3 to about 10 carbon atoms by removing a hydrogen atom from each of two different carbon atoms of the ring.
  • exemplary cycloalkenylene radicals include cyclopentylene and cyclohexylene.
  • Halo or halogen means fluoro, chloro, bromo, or iodo. Preferred are fluoro or chloro.
  • exemplary groups include pyridylcarbonyl.
  • Heteroaroylamino means a heteroaroyl-NH- group in which the heteroaryl moiety are as previously described.
  • Heteroaryl as a group or part of a group denotes: (i) a aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulphur (examples of such groups include benzimidazolyl, benzthiazolyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups, optionally substituted by one or more aryl group substituents as defined above
  • Heteroarylalkenyl means a heteroaryl-alkenyl- group in which the heteroaryl and alkenyl moieties are as previously described. Preferred heteroarylalkenyl groups contain a lower alkenyl moiety. Exemplary heteroarylalkenyl groups include pyridylethenyl and pyridylallyl.
  • Heteroarylalkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a C 1-4 alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.
  • Heteroarylalkyloxy means an heteroarylalkyl-O- group in which the heteroarylalkyl group is as previously described.
  • exemplary heteroaryloxy groups include pyridylmethoxy.
  • Heteroarylalkynyl means a heteroaryl-alkynyl- group in which the heteroaryl and alkynyl moieties are as previously described.
  • exemplary heteroarylalkenyl groups include pyridylethynyl and 3-pyridylbut-2-ynyl.
  • Heteroaryldiyl means a bivalent radical derived from an aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulphur.
  • Ar 1 is a heteroaryldiyl group this may particularly represent an "azaheteroaryldiyl” group.
  • Heteroaryloxy means an heteroaryl-O- group in which the heteroaryl group is as previously described.
  • exemplary heteroaryloxy groups include pyridyloxy.
  • Heterocycloalkyl means: (i) a cycloalkyl group of about 3 to 7 ring members which contains one or more heteroatoms selected from O, S or NY 3 ; (ii) a partially saturated multicyclic heterocarbocyclic moiety in which an aryl (or heteroaryl ring) and a heterocycloalkyl group are fused together to form a cyclic structure (examples of such groups include chromanyl, dihydrobenzofuranyl, indolinyl and pyrindolinyl groups).
  • Heterocycloalkylalkyl means a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as previously described.
  • Heterocycloalkylene means a bivalent radical derived from a saturated monocyclic hydrocarbon of about 5 to about 7 atoms, which contains one or more heteroatoms selected from O, S or NY 3 . Such a radical may be substituted by oxo, by removing a hydrogen atom from each of two different carbon atoms of the ring, or when NY 3 is NH by removing a hydrogen atom from one carbon atom of the ring and a hydrogen atom from the NH, or when the ring contains two NY 3 heteroatoms and NY 3 is NH by removing a hydrogen atom from both nitrogen atoms.
  • L 1 is a heterocycloalkylene group this may particularly represent a bivalent radical derived pyrrolidine, especially 3,4-pyrrolidinediyl.
  • Prodrug means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of formula (I), including N-oxides thereof.
  • an ester of a compound of formula (I) containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • an ester of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • Suitable esters of compounds of formula (I) containing a hydroxy group are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis- ⁇ -hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
  • Suitable esters of compounds of formula (I) containing a carboxy group are for example those described by F.J.Leinweber, Drug Metab. Res., 1987, 18 , page 379.
  • Suitable esters of compounds of formula (I) containing both a carboxy group and a hydroxy group within the moiety -L 1 -Y include lactones, formed by loss of water between said carboxy and hydroxy groups.
  • lactones include caprolactones and butyrolactones.
  • esters of compounds of formula (I) containing a hydroxy group may be formed from acid moieties selected from those described by Bundgaard et. al., J. Med. Chem., 1989, 32 , page 2503-2507, and include substituted (aminomethyl)-benzoates, for example dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, more especially (morpholino-methyl)benzoates, e.g. 3- or 4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-1-yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-1-yl)benzoates.
  • substituted (aminomethyl)-benzoates for example dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen
  • base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form.
  • the bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the cations.
  • Pharmaceutically acceptable salts including those derived from alkali and alkaline earth metal salts, within the scope of the invention include those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, and the like.
  • Some of the compounds of the present invention are basic, and such compounds are useful in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt thereof.
  • Acid addition salts are a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form.
  • the acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the anions.
  • compositions are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures.
  • Pharmaceutically acceptable salts within the scope of the invention include those derived from mineral acids and organic acids, and include hydrohalides, e.g.
  • hydrochlorides and hydrobromides sulphates, phosphates, nitrates, sulphamates, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methane-sulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
  • salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.
  • arylalkyl in which the aryl group is optionally substituted by one, or preferably two aryl group substituents (preferred optional substituents include halo, hydroxy and methoxy).
  • L 4 represents a straight or branched C 1-6 alkylene chain, more particularly a straight C 1-4 alkylene chain such as methylene or ethylene, preferably methylene;
  • Ar 1 is an optionally substituted phenylene, such as optionally substituted m- or p-phenylene, preferably optionally substituted p-phenylene, more preferably a 3-substituted p-phenylene, in which the substituent is ortho to the R 3 -L 3 - group, (preferred optional substituents include halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylsulphinyl and C 1-4 alkylsulphonyl, especially chloro, methyl, methoxy, methylthio, methylsulphinyl and methyl
  • optionally substituted pyridinediyl preferably a p-pyridinediyl
  • the optional substituents include C 1-4 alkyl and C 1-4 alkoxy, especially methyl and methoxy, more preferably a pyridine-2,5-diyl, in which the R 3 -L 3 - group is adjacent to the pyridyl nitrogen atom, and which is substituted in the 4- or 6-position with a methyl or methoxy group
  • R 3 is as defined above, particularly an aryl group (such as optionally substituted phenyl) or an heteroaryl (such as optionally substituted pyridyl), and is preferably 2- or 3-methyl(or methoxy)phenyl, more preferably 2-methylphenyl, or 3-methyl-2-pyridyl.
  • L 3 represents NR 5 , especially NH; and R 3 is as defined above, particularly aryl, such as a 2-substituted phenyl, [examples of particular aryl group substituents include lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy), halo (e.g. fluoro or chloro) and Y 1 Y 2 N-(e.g. dimethylamino)], and is preferably 2-methylphenyl.
  • aryl such as a 2-substituted phenyl
  • optionally substituted pyridinediyl preferably a p-pyridinediyl
  • the optional substituents include C 1-4 alkyl and C 1-4 alkoxy, especially methyl and methoxy, more preferably a pyridine-2,5-diyl, in which the R 3 -L 3 - group is adjacent to the pyridyl nitrogen atom, and which is substituted in the 4- or 6-position with a methyl or methoxy group
  • R 2 may particularly represent hydrogen.
  • R 2 may also particularly represent lower alkyl, (e.g. methyl).
  • R 2 may also particularly represent lower alkoxy (e.g. methoxy).
  • a 1 may particularly represent an unsubstituted straight chain C 1-2 alkylene linkage, i.e. methylene or ethylene.
  • Z 1 may particularly represent C(R 7 )(R 7a ), especially where R 7 and R 7a are both hydrogen.
  • L 1 may particularly represent an optionally substituted alkylene linkage, especially optionally substituted ethylene or propylene, preferably optionally substituted ethylene.
  • L 1 may also particularly represent an unsubstituted alkenylene linkage, especially vinylene.
  • L 1 may also particularly represent a -Z 2 -R 12 - linkage, such as -O-CH 2 -, -S(O) n -CH 2 -, -S(O) n -CH 2 -CH 2 -, or especially -NH-CH 2 -.
  • a -Z 2 -R 12 - linkage such as -O-CH 2 -, -S(O) n -CH 2 -, -S(O) n -CH 2 -CH 2 -, or especially -NH-CH 2 -.
  • L 1 may also particularly represent a -L 5 -L 6 -L 7 - linkage, in which (i) L 5 and L 7 are both a direct bond and L 6 is heterocycloalkylene, such as pyrrolidindiyl, especially 3,4-pyrrolidindiyl, or cycloalkylene, such as cyclopentyl, (ii) L 5 is alkylene, such as methylene, L 6 is cycloalkylene, such as cyclopentyl, and L 7 is a direct bond, or (iii) L 5 is a direct bond, L 6 is cycloalkylene, such as cyclopentyl, and L 7 is alkylene, such as methylene.
  • L 5 and L 7 are both a direct bond and L 6 is heterocycloalkylene, such as pyrrolidindiyl, especially 3,4-pyrrolidindiyl, or cycloalkylene, such as cyclopentyl
  • L 5 is alky
  • a particular group of compounds of the invention are compounds of formula (Ix):- wherein:-
  • Another particular group of compounds of the invention are compounds of formula (Ia):- in which R 2 , R 3 , A 1 , Ar 1 , L 1 , L 4 , Y and Z 1 are as hereinbefore defined, and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  • R 3 represents an aryl group, particularly an optionally substituted phenyl group, such as a 2-substituted phenyl, especially 2-methylphenyl, are preferred.
  • R 3 represents an heteroaryl group, particularly an optionally substituted pyridyl, such as optionally substituted 2-pyridyl, especially 3-methyl-2-pyridyl, are also preferred.
  • Preferred optional substituents include halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylsulphinyl and C 1-4 alkylsulphonyl, especially chloro, methyl, methoxy, methylthio, methylsulphinyl and methylsulphonyl.
  • Preferred optional substituents include C 1-4 alkyl and C 1-4 alkoxy, especially methyl and methoxy.
  • L 4 represents a straight or branched C 1-6 alkylene chain, more particularly a straight C 1-4 alkylene chain such as methylene or ethylene, especially methylene, are preferred.
  • R 2 is hydrogen
  • R 3 is a 2-substituted phenyl [especially 2-methyl(or methoxy)phenyl]
  • a 1 is methylene or ethylene
  • Ar 1 is optionally substituted m- or p-phenylene (especially 3-chloro-p-phenylene, 3-methyl-p-phenylene, 3-methoxy-p-phenylene, 3-methylthio-p-phenylene, 3-methylsulphinyl-p-phenylene and 3-methylsulphonyl-p-phenylene) or optionally substituted p-pyridinediyl [especially 4(or 6)-methyl(or methoxy)-p-pyridine-2,5-diyl];
  • R 2 , R 3 , A 1 , L 2 , Y and Z 1 are as hereinbefore defined
  • X is NR 5 or O
  • Z 4 represents a direct bond, NR 5 , O or S(O) n (where R 5 and n are as hereinbefore defined)
  • R is hydrogen or an aryl group substituent, and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  • R 3 represents aryl, especially 2-substituted phenyl
  • Preferred optional substituents include lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy), halo (e.g. fluoro or chloro) and Y 1 Y 2 N- (e.g. dimethylamino).
  • R 3 especially represents ortho-tolyl.
  • R represents hydrogen, halo (e.g. chloro), lower alkyl (e.g. methyl or ethyl) or lower alkoxy (e.g. methoxy) are preferred.
  • the group may preferably be attached at the ring 6 position or the ring 5 or 6 position when X is NR 5 and R 5 is lower alkyl.
  • R is hydrogen, chloro, methyl, ethyl or methoxy
  • R 2 is hydrogen
  • R 3 is aryl (especially ortho-tolyl)
  • a 1 is methylene or ethylene
  • L 4 is a straight or branched C 1-4 alkylene chain, especially methylene
  • X is O
  • Y is carboxy
  • Z 1 is CH 2
  • Z 4 is NH
  • the group is attached at the ring 6 position; and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  • R 2 is hydrogen
  • R 3 is aryl (especially ortho-tolyl)
  • a 1 is methylene or ethylene
  • R 2 is hydrogen
  • R 3 is aryl (especially ortho-tolyl)
  • a 1 is methylene or ethylene
  • L 4 is a straight or branched C 1-4 alkylene chain, (especially methylene)
  • X is NR 5 (especially NH)
  • Y is carboxy
  • Z 1 is CH 2
  • Z 4 is NH
  • the group is attached at the ring 5 or 6 position; and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  • Another particular group of compounds of the invention are compounds of formula (Ic):- in which Ar 1 , L 4 , A 1 , R 2 , L 1 , Y and Z 1 are as hereinbefore defined, and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  • Ar 1 is an heteroaryldiyl, such as optionally substituted pyridinediyl, particularly a p-pyridinediyl, more particularly a pyridine-2,5-diyl, in which the group is adjacent to the pyridyl nitrogen atom, and which is substituted in the 4- or 6-position, are also preferred.
  • Preferred optional substituents include C 1-4 alkyl and C 1-4 alkoxy, especially methyl and methoxy.
  • R 2 is hydrogen
  • a 1 is methylene or ethylene
  • Ar 1 is optionally substituted m- or p-phenylene (especially 3-chloro-p-phenylene, 3-methyl-p-phenylene, 3-methoxy-p-phenylene, 3-methylthio-p-phenylene, 3-methylsulphinyl-p-phenylene and 3-methylsulphonyl-p-phenylene) or optionally substituted p-pyridinediyl [especially 4(or 6)-methyl(or methoxy)-p-pyridine-2,5-diyl];
  • Another particular group of compounds of the invention are compounds of formula (Id):- in which R 3 , A 1 , R 2 , L 1 , Y and Z 1 are as hereinbefore defined, and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  • R 3 represents aryl, especially optionally substituted phenyl
  • Preferred optional substituents include aryloxy, cyano, halo (e.g. chloro or fluoro), lower alkoxy (e.g. methoxy), lower alkyl (e.g. methyl), nitro and perfluoroloweralkyl (e.g. trifluoromethyl).
  • R 3 especially represents 2-chlorophenyl, 5-chloro-2-cyanophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 4-fluoro-2-trifluoromethyl, 2-methyl-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2-nitrophenyl, 3-nitrophenyl and 2-phenoxyphenyl.
  • R 3 represents heteroaryl, especially isoquinolinyl, isoxazolyl, pyrazolopyrimidinyl, pyridyl, pyrimidinyl, quinolinyl, thiazolyl and triazolyl, each optionally substituted by one or more aryl group substituents, are preferred.
  • R 3 especially represents quinolin-4-yl, isoquinolin-2-yl, 2,4-pyridin-3-yl, 2,6-dimethyl-4-trifluoromethylpyridin-3-yl, 4-trifluoromethylpyridin3-yl, 2-phenyl-4-methyl-1,2,3-triazol-5-yl, 3,5-dimethylisoxazol-4-yl, 2,7-dimethylpyrazolofl,5-a]pyrimidin-6-yl, 2-isopropyl-4-methylthiazol-5-yl and 4-tritluoromethylpyrimidin-5-yl.
  • R 3 represents arylalkyl
  • R 3 especially represents optionally substituted benzyl, particularly 4-hydroxybenzyl, 3-chloro-4-hydroxybenzyl, 3-fluoro-4-hydroxybenzyl and 4-hydroxy-3-methoxybenzyl.
  • a preferred group of compounds of the invention are compounds of formula (Id) in which:- R 2 is hydrogen; R 3 is optionally substituted phenyl (especially 2-chlorophenyl, 5-chloro-2-cyanophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 4-fluoro-2-trifluoromethyl, 2-methyl-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2-nitrophenyl, 3-nitrophenyl and 2-phenoxyphenyl), heteroaryl (especially quinolin-4-yl, isoquinolin-2-yl, 2,4-pyridin-3-yl, 2,6-dimethyl-4-trifluoromethylpyridin-3-yl, 4-trifluoromethylpyridin3-yl, 2-phenyl-4-methyl-1,2,3-triazol-5-yl, 3,5-dimethylisoxazol-4-yl, 2,7-dimethylpyrazol
  • R 2 is hydrogen
  • R 3 is optionally substituted phenyl (especially 2-chlorophenyl, 5-chloro-2-cyanophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 4-fluoro-2-trifluoromethyl, 2-methyl-4-nitrophenyl, 2-inethyl-5-nitrophelay4 2-nitrophenyl, 3-nitrophenyl and 2-phenoxyphenyl), heteroaryl (especially quinolin-4-yl, isoquinolin-2-yl, 2,4-pyridin-3-yl, 2,6-dimethyl-4-trifluoromethylpyridin-3-yl, 4-trifluoromethylpyridin3-yl, optionally substituted benzyl (especially 4-hydroxybenzyl, 3-chloro-4-hydroaybenzyl, 3-fluoro-4-hydroxybenzyl and 4-
  • R 15 represents lower alkyl (e.g. methyl, ethyl, propyl, butyl) are also preferred.
  • alkyl substituted by carboxy e.g. -CH 2 -CH 2 -CO 2 H and -CH 2 -CH 2 -CH 2 -CO 2 H
  • alkyl substituted by -NY 4 Y 5 e.g. aminomethyl and morpholin-1-ylmethyl
  • R 15 represents -N(R 8 )-SO 2 -R 9 , especially where R 8 is hydrogen or lower alkyl (e.g. methyl) and R 9 is lower alkyl (e.g. methyl), aryl [e.g. optionally substituted phenyl or optionally substituted naphthyl (especially dimethylaminonaphth-1-yl)]), heteroaryl (e.g. optionally substituted pyridyl or optionally substituted imidazolyl), are also preferred.
  • R 8 is hydrogen or lower alkyl (e.g. methyl) and R 9 is lower alkyl (e.g. methyl)
  • R 9 is lower alkyl (e.g. methyl)
  • aryl e.g. optionally substituted phenyl or optionally substituted naphthyl (especially dimethylaminonaphth-1-yl)
  • heteroaryl e.g. optionally substituted pyridyl or optionally substituted imi
  • R 15 represents -NY 4 Y 5 , especially where Y 4 is hydrogen and Y 5 is or lower alkyl (e.g. propyl), or alkyl substituted by aryl (e.g. -CH 2 -Ph or -CH 2 -CH 2 -Ph), are also preferred.
  • R 15 represents -NY 4 Y 5 , especially where Y 4 and Y 5 represent alkyl substituted by aryl (e.g. -CH 2 -Ph or -CH(CH 3 )-Ph), are also preferred.
  • R 15 represents alkyl substituted by carboxy, especially lower alkyl substituted by carboxy (e.g. carboxymethyl), are also preferred.
  • R 15 represents alkyl substituted by -OH, especially lower alkyl substituted by -OH (e.g. hydroxymethyl), are also preferred.
  • R 15 represents alkyl substituted by -OR 3 , especially lower alkyl substituted by -OR 3 (e.g. methoxymethyl), are also preferred.
  • Particularly preferred compounds of formula (Ia), (Ib), (Ic) and (Id) are those in which R 15 is -H, -NH 2 , -NHCH 2 CH 2 CH 3 , (in which R is hydrogen or an aryl group substituent), -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 -OH, -CH 2 -CO 2 H or -CH 2 -OMe.
  • alkyl substituted by carboxy e.g. -CH 2 -CH 2 -CO 2 H and -CH 2 -CH 2 -CH 2 -CO 2 H
  • alkyl substituted by -NY 4 Y 5 e.g. aminomethyl and morpholin-1-ylmethyl
  • Particular compounds of the invention are selected from the compounds formed by joining the acyl carbon atom (C*) of one of the fragments (A1 to A34) shown in Table 1 to the nitrogen atom (N*) of one of the aza-bicyclic fragments (B1 to B6) shown in Table 2, and joining the carbon atom (C*) of the phenyl ring in one of the aza-bicyclic fragments (B1 to B6) shown in Table 2 to the carbon atom (C*) of one of the acidic fragments (C1 to C59) depicted in Table 3.
  • Particular compounds of the invention are:- and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  • the compound denoted as A1-B1-C1 is the product of the combination of group A1 in Table 1 and B1 in Table 2 and C1 in Table 3, namely
  • Preferred compounds of the invention are:-
  • the compounds of the invention exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders.
  • the present invention thus provides, according to a further aspect, compounds of the invention and compositions containing compounds of the invention for use in therapy.
  • the present invention provides compounds of the invention and compositions containing compounds of the invention for use in the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of ⁇ 4 ⁇ 1 mediated cell adhesion.
  • compounds of the present invention are useful in the treatment of inflammatory diseases, for example joint inflammation, including arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and osteoarthritis.
  • the compounds may be useful in the treatment of acute synovitis, autoimmune diabetes, autoimmune encephalomyelitis, collitis, atherosclerosis, peripheral vascular disease, cardiovascular disease, multiple sclerosis, asthma, psoriasis restenosis, myocarditis, inflammatory bowel disease and melanoma cell division in metastasis.
  • a special embodiment of the therapeutic methods of the present invention is the treating of asthma.
  • Another special embodiment of the therapeutic methods of the present invention is the treating of joint inflammation.
  • Another special embodiment of the therapeutic methods of the present invention is the treating of inflammatory bowel disease.
  • Effective amount is meant to describe an amount of compound of the present invention effective in inhibiting the interaction of the ligand VCAM-1 to its integrin receptor VLA-4( ⁇ 4 ⁇ 1), and thus producing the desired therapeutic effect.
  • references herein to treatment should be understood to include prophylactic therapy as well as treatment of established conditions.
  • the present invention also includes within its scope pharmaceutical compositions comprising at least one of the compounds of the invention in association with a pharmaceutically acceptable carrier or excipient.
  • Compounds of the invention may be administered by any suitable means.
  • compounds of the present invention may generally be administered parenterally, topically, rectally, orally or by inhalation, especially by the oral route.
  • compositions according to the invention may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients.
  • the adjuvants comprise, inter alia, diluents, sterile aqueous media and the various non-toxic organic solvents.
  • the compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and can contain one or more agents chosen from the group comprising sweeteners, flavourings, colourings, or stabilisers in order to obtain pharmaceutically acceptable preparations.
  • the choice of vehicle and the content of active substance in the vehicle are generally determined in accordance with the solubility and chemical properties of the active compound, the particular mode of administration and the provisions to be observed in pharmaceutical practice.
  • excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used for preparing tablets.
  • lactose and high molecular weight polyethylene glycols it is advantageous to use lactose and high molecular weight polyethylene glycols.
  • aqueous suspensions When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension.
  • Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.
  • emulsions, suspensions or solutions of the products according to the invention in vegetable oil for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, are used.
  • vegetable oil for example sesame oil, groundnut oil or olive oil
  • aqueous-organic solutions such as water and propylene glycol
  • injectable organic esters such as ethyl oleate
  • sterile aqueous solutions of the pharmaceutically acceptable salts are used.
  • the solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection.
  • aqueous solutions also comprising solutions of the salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilised by heating, irradiation or microfiltration.
  • gels water or alcohol based
  • creams or ointments containing compounds of the invention may be used.
  • Compounds of the invention may also be incorporrated in a gel or matrix base for application in a patch, which would allow a controlled release of compound through the transdermal barrier.
  • inhalation compounds of the invention may be dissolved or suspended in a suitable carrier for use in a nebuliser or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler.
  • Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of the invention.
  • the percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time.
  • the dose employed will be determined by the physician, and depends upon the desired therapeutic effect the route of administration and the duration of the treatment, and the condition of the patient, In the adult, the doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation, from about 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from about 0.001 to about 10, preferably 0.01 to 1, mg/kg body weight per day by intravenous administration. In each particular case, the doses will be determined in accordance with the factors distinctive to the subject to be treated, such as age, weight, general state of health and other characteristics which can influence the efficacy of the medicinal product.
  • the compounds according to the invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. Of course, for some patients, it will be necessary to prescribe not more than one or two doses per day.
  • the hydrolysis of the esters may also be carried out by acid hydrolysis using an inorganic acid, such as hydrochloric acid, in the presence of an aqueous/inert organic solvent mixture, using organic solvents such as dioxan or tetrahydrofuran, at a temperature from about 50°C to about 80°C.
  • compounds of formula (I), wherein R 1 , R 2 , A 1 , L 1 and Z 1 are as hereinbefore defined, and where Y is carboxy may be prepared by acid catalysed removal of the tert-butyl group of tert-butyl esters of formula (I), wherein R 1 , R 2 , A 1 , L 1 and Z 1 are as hereinbefore defined and Y is a -CO 2 R 16 group (in which R 16 is tert-butyl), using standard reaction conditions, for example reaction with trifluoroacetic acid at a temperature at about room temperature.
  • compounds of formula (I), wherein R 1 , R 2 , A 1 , L 1 and Z 1 are as hereinbefore defined, and where Y is carboxy may be prepared by hydrogenation of compounds of formula (I) wherein R 1 , R 2 , A 1 , L 1 and Z 1 are as hereinbefore defined and Y is a -CO 2 R 16 group (in which R 16 is arylmethyl, e.g. benzyl).
  • the reaction may be carried out in the presence of ammonium formate and a suitable metal catalyst, e.g. palladium, supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol and at a temperature at about reflux temperature.
  • a suitable metal catalyst e.g. palladium
  • the reaction may alternatively be carried out in the presence of a suitable metal catalyst, e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol.
  • a suitable metal catalyst e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol.
  • This reaction is most suitable for compounds of formula (I) where L 1 does not contain carbon-carbon multiple bonds.
  • a compounds of formula (I), containing an amide bond may be prepared by coupling of an acid (or an acid halide) with an amine to give an amide bond using standard peptide coupling procedures as described hereinafter.
  • R 1 is a group selected from R 3 -Z 3 -, R 3 -L 2 -R 4 -Z 3 -, R 3 -L 3 -Ar 1 -L 4 -Z 3 - or R 3 -L 3 -Ar 1 -L 2 -R 4 -Z 3 - [in which R 3 , R 4 , L 2 , L 3 , L 4 and Ar 1 are as hereinbefore defined and
  • Esters of formula (I), wherein R 2 , A 1 , L 1 and Z 1 are as hereinbefore defined, R 1 is a group selected from R 3 -Z 3 -, R 3 -L 2 -R 4 -Z 3 -, R 3 -L 3 -Ar 1 -L 4 -Z 3 - or R 3 -L 3 -Ar 1 -L 2 -R 4 -Z 3 - [in which R 3 , R 4 , L 2 , L 3 , L 4 and Ar 1 are as hereinbefore defined and Z 3 is C( O)] and Y is a -CO 2 R 16 group (in which R 16 is as hereinbefore defined), may be prepared by reacting a compound of formula (III) wherein R 18 is R 3 -, R 3 -L 2 -R 4 -, R 3 -L 3 -Ar 1 -L 4 - or R 3 -L 3 -Ar 1 -L 2 -R 4 - (in which R
  • Esters of formula (I), wherein R 1 , R 2 , A 1 and Z 1 are as hereinbefore defined, Y is a -CO 2 R 16 group (in which R 16 is as hereinbefore defined) and L 1 contains a -N(R 8 )-SO 2 -R 9 group (in which R 8 and R 9 are as hereinbefore defined), may be similarly prepared from the corresponding esters of formula (I) where L 1 contains a -NHR 8 group (in which R 8 is as hereinbefore defined) by reaction with sulphonyl chlorides of formula R 9 -SO 2 Cl wherein R 9 is as hereinbefore defined.
  • the reaction may be carried out in the presence of formic acid and a suitable metal catalyst, e.g. palladium, supported on an inert carrier such as carbon, at a temperature at about 60°C.
  • the reaction may conveniently be carried out in the presence of a suitable metal catalyst, e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol.
  • Esters of formula (I), wherein R 1 , R 2 , A 1 and Z 1 are as hereinbefore defined, Y is a -CO 2 R 16 group (in which R 16 is as hereinbefore defined) and L 1 is a (or linkage, may also be obtained from the racemic mixture following standard recrystallisation of a suitable salt (for example recrystallisation of the tartrate salt), or by the application of standard enzymatic resolution procedures (for example those described by Soloshonok, V. A., et. al., Tetrahedron: Asymmetry 6 (1995) 7,1601-1610).
  • an alkali metal hydride such as sodium hydride
  • Esters of formula (I), wherein R 1 , R 2 , A 1 and Z 1 are as hereinbefore defined, Y is a -CO 2 R 16 group (in which R 16 is as hereinbefore defined) and L 1 contains an alkenylene, alkynylene or cycloalkenylene in which the aliphatic carbon-carbon multiple bond is attached directly to the phenyl moiety in formula (I), may be prepared by coupling of compounds of formula (IX):- wherein R 1 , R 2 , A 1 and Z 1 are as hereinbefore defined and X 4 is a halogen, preferably bromine or iodine, atom with a compound of formula (X):- R 19 -CO 2 R 16 (X) wherein R 16 is as hereinbefore defined and R 19 is alkenyl, alkynyl or cycloalkenyl When X 4 is a bromine or iodine atom the reaction may be conveniently carried out in the presence of palladium acetate,
  • This reaction is particularly suitable for the preparation of esters of formula (I) in which L 1 is vinylene.
  • X 4 is a chlorine atom the reaction may be conveniently carried out in the presence of sodium iodide, nickel bromide, palladium(0) bis(dibenzylideneacetone), a triarylphosphine, such as tri-o-tolylphosphine, and a tertiary amine, such as tributylamine, at a temperature up to about 110°C.
  • Compounds of the invention may be prepared by interconversion of other compounds of the invention.
  • compounds of formula (I) containing sulphoxide linkages may be prepared by the oxidation of corresponding compounds containing -S- linkages.
  • the oxidation may conveniently be carried out by means of reaction with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature, or alternatively by means of potassium hydrogen peroxomonosulphate in a medium such as aqueous methanol, buffered to about pH5, at temperatures between about 0°C and room temperature.
  • a peroxyacid e.g. 3-chloroperbenzoic acid
  • an inert solvent e.g. dichloromethane
  • potassium hydrogen peroxomonosulphate in a medium such as aqueous methanol, buffered to about pH5, at temperatures between about 0°C and room temperature.
  • This latter method is preferred for compounds containing an acid-labile group.
  • compounds of formula (I) containing sulphone linkages may be prepared by the oxidation of corresponding compounds containing -S- or sulphoxide linkages.
  • the oxidation may conveniently be carried out by means of reaction with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature.
  • compounds of formula (I), wherein R 1 , R 2 , A 1 , Z 1 and Y are as hereinbefore defined, and L 1 is optionally substituted alkylene may be prepared by hydrogenation of the corresponding compounds of formula (I) in which L 1 is the corresponding optionally substituted alkenylene.
  • the hydrogenation may be carried out using hydrogen (optionally under pressure) in the presence of a suitable metal catalyst, e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol, and at a temperature at about room temperature.
  • compounds of formula (I), wherein R 1 , R 2 , A 1 , L 1 and Z 1 are as hereinbefore defined, L 1 is an alkylene linkage substituted by -CONY 4 Y 5 and Y is carboxy may be prepared by reacting compounds of formula (I), wherein R 1 , R 2 , A 1 , L 1 and Z 1 are as hereinbefore defined, L 1 is an alkylene linkage substituted by -CO 2 H and Y is carboxy, with an anhydride, such as trifluoroacetic anhydride, in an inert solvent e.g. tetrahydrofuran, followed by treatment with an amine HNY 4 Y 5 .
  • anhydride such as trifluoroacetic anhydride
  • the oxidation may conveniently be carried out by reaction with potassium permanganate.
  • the reduction may conveniently be carried out by reaction with sodium borohydride in aqueous ethanol at a temperature at about room temperature.
  • compounds of the invention containing a heterocyclic group wherein the hetero atom is a nitrogen atom may be oxidised to their corresponding N-oxides.
  • the oxidation may conveniently be carried out by means of reaction with a mixture of hydrogen peroxide and an organic acid, e.g. acetic acid, preferably at or above room temperature, for example at a temperature of about 60-90°C.
  • the oxidation may be carried out by reaction with a peracid, for example peracetic acid or m-chloroperoxybenzoic acid, in an inert solvent such as chloroform or dichloromethane, at a temperature from about room temperature to reflux, preferably at elevated temperature.
  • the oxidation may alternatively be carried out by reaction with hydrogen peroxide in the presence of sodium tungstate at temperatures between room temperature and about 60°C.
  • compounds of the present invention may contain asymmetric centres. These asymmetric centres may independently be in either the R or S configuration. It will be apparent to those skilled in the art that certain compounds of the invention may also exhibit geometrical isomerism. It is to be understood that the present invention includes individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures, of compounds of formula (I) hereinabove. Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallisation techniques, or they are separately prepared from the appropriate isomers of their intermediates.
  • acid addition salts of the compounds of this invention may be prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods.
  • the acid addition salts of the compounds of this invention may be prepared either by dissolving the free base in water or aqueous alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
  • the acid addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods.
  • parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
  • parent compounds of the invention can be regenerated from their base addition salts by the application or adaptation of known methods.
  • parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.
  • Hydrates of compounds of the present invention may be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallisation from an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol.
  • base addition salts of the compounds of this invention may be prepared by reaction of the free acid with the appropriate base, by the application or adaptation of known methods.
  • the base addition salts of the compounds of this invention may be prepared either by dissolving the free acid in water or aqueous alcohol solution or other suitable solvents containing the appropriate base and isolating the salt by evaporating the solution, or by reacting the free acid and base in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
  • the starting materials and intermediates may be prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their obvious chemical equivalents.
  • a carbodiimide such as dicyclohexylcarbodiimide or diisopropylcarbodiimide in
  • Acids of formula (III) wherein R 18 is R 3 -L 3 -Ar 1 -L 4 - (in which R 3 and L 4 are as hereinbefore defined, Ar 1 is (in which R is as hereinbefore defined), L 3 is NH and X 1 is hydroxy may be similarly prepared from compounds of formula (1) wherein R, L 4 and R 16 are as hereinbefore defined and X is NH.
  • Acid chlorides of formula (III) wherein R 18 is as hereinbefore defined and X 1 is a chlorine atom may be prepared from the corresponding acids of formula (II) wherein R 18 is as hereinbefore defined and X 1 is hydroxy, by the application of standard procedures for the conversion of acids to acid chlorides for example by reaction with oxalyl chloride.
  • Compounds of formula (2), wherein R 2 and R 16 are as hereinbefore defined and L 1 is alkylene may be prepared by an electrochemical coupling reaction between a compound of formula (3):- wherein R 2 is as hereinbefore defined and X 5 is iodo, or preferably bromo, and an alkenoic ester of formula (X) wherein R 16 is as hereinbefore defined and R 20 is alkenyl.
  • the reaction may conveniently be carried out in the presence of nickel salt catalyst, such as nickel bromide trihydrate, tetrabutylammonium bromide, tetrabutylammonium iodide and 1,2-dibromoethane, in an inert solvent, or a mixture of inert solvents, such as dimethylformamide and pyridine, and at a temperature at about 60°C.
  • nickel salt catalyst such as nickel bromide trihydrate, tetrabutylammonium bromide, tetrabutylammonium iodide and 1,2-dibromoethane
  • inert solvent or a mixture of inert solvents, such as dimethylformamide and pyridine
  • Compounds of formula (2) wherein R 2 and R 16 are as defined hereinbefore and L 1 is alkenylene, alkynylene or cycloalkenylene in which the carbon-carbon multiple bond is attached directly to the phenyl moiety in formula (I), may be prepared by reacting a compound of formula (3) wherein R 2 is as hereinbefore defined and X 5 is an iodine, or preferably a bromine, atom with a compound of formula (X) wherein R 16 and R 19 are as hereinbefore defined using standard Heck coupling reaction conditions, for example reaction in the presence of palladium acetate, triphenylphosphine and tributylamine at a temperature up to about 120°C.
  • Compounds of formula (2) wherein R 2 and R 16 are as defined hereinbefore and L 1 is an optionally substituted arylene or an optionally substituted heteroaryldiyl linkage, may be prepared by reacting a compound of formula (3) wherein R 2 is as hereinbefore defined and X 5 is iodo or bromo with a compound of formula (4):- Br-L 1 -CO 2 R 16 (4) wherein R 16 are as defined hereinbefore and L 1 is an optionally substituted arylene or an optionally substituted heteroaryldiyl linkage in the presence of a complex metal catalyst such as tetrakis(triphenylphosphine)palladium(0), using standard reaction conditions, for example those described by Trecourt et al, Tetrahedron, 51 (1995) 43, pages11743-11750.
  • a complex metal catalyst such as tetrakis(triphenylphosphine)palladium(0)
  • the cross-coupling reaction may conveniently be carried out in the presence of palladium acetate and tris(o-tolyl)phosphine using standard coupling conditions such as those described hereinbefore.
  • a suitable protecting group for the NH group is for example a tertiary-butyloxycarbonyl group.
  • Compounds of formula (7) wherein R 2 is hydrogen, A 1 is ethylene, Z 1 is CH 2 and X 6 is an iodine atom attached to the 6 position of the tetrahydroquinoline ring may be prepared by iodination of 1,2,3,4-tetrahydroquinoline with iodine monochloride in acetic acid at a temperature at about room temperature.
  • the present invention is further Exemplified but not limited by the following illustrative Examples and Reference Examples.
  • Mass spectra (MS) for Example 4(b) and for the Reference Examples (unless otherwise indicated) were recorded on a Micromass Platform II mass spectrometer fitted with an Electrospray source and an HP1100 liquid chromatograph; using a mixture of acetonitrile and water (1:1, v/v) as the mobile phase, a flow rate of 0.3 ml/minute, an injection volume of 20 ⁇ l, a run time of 2.0 minutes, a scan range of 150 - 850 Daltons Positive/Negative, a scan time of 2.0 seconds, an ESI voltage of 3.5Kv, an ESI pressure of 20n/m2 Nitrogen.
  • Mass spectra [MS(ES + )] for the Examples 1 - 12 were recorded on a Micromass LCT Mass Spectrometer (Orthogonal Acceleration Time of Flight Mass Spectrometer), with the Z-Flow Atmospheric pressure ionisation source operating in positive ion electrospray mode (ES + ), connected to an HP1100 liquid chromatograph.
  • the conditions used were as follows: 3 micron Luna C18 HPLC column (30mm x 4.6mm) operated under gradient elution conditions with a mixture of acetonitrile and water as the mobile phase gradient: 0.00 minutes, 95% water:5% acetonitrile; 0.50 minutes, 95% water:5% acetonitrile; 4.50 minutes, 5% water:95% acetonitrile; 5.00 minutes, 5 % water :95 % acetonitrile; 5.50 minutes, 95 % water :5% acetonitrile; flow rate 2ml/minutewith approximately 200ml/minute split to the Mass Spectrometer; injection volume 10-40ml; in line Diode Array detection (220-450nm), in line Evaporative light scattering (ELS) detection ELS - temperature 50°C, Gain 8 - 1.8ml/minute; Source temperature 150°C.
  • the resulting white foamy solid (0.457g) was subjected to flash chromatography on silica (0,040-0,063mm) eluting with a mixture of cyclohexane and ethyl acetate (250ml, 9:1, then 500ml, 7:3, then 1000ml, 4:6; v/v) to give the title compound (0.244g) as a white foamy solid.
  • a stirred mixture of ethyl 3-(6-quinolinyl)propanoate (0.3g, Reference Example 3) in hydrochloric acid (3ml, 0.1N) and 5% rhodium in carbon powder (33mg) was hydrogenated in a 22 cm 3 stainless steel pressure reactor at a pressure of 50 bars of hydrogen. After stirring for 4 hours at 25°C a further portion of 30 mg of 5% rhodium in carbon powder (33mg) was added and the hydrogenation was continued under a pressure of 50 bars at 25°C for 1 hour.
  • the reaction mixture was filtered through a pad of celite and the filter pad was washed with hydrochloric acid (3ml, 0.1N) then with ethyl acetate (25ml).
  • the combined filtrate and washings were combined and the aqueous phase was decanted from the organic phase.
  • the aqueous phase was extracted twice with ethyl acetate (25ml) and combined with the aforementioned organic phase.
  • the combined solutions were dried over magnesium sulfate then evaporated under reduced pressure (2. kPa) at 40°C to give the title compound (0.121g) as a brown oil.
  • the reaction medium was heated to 60°C and then electrolysis was carried out using a constant current of 250mA whilst maintaining the temperature at 60°C. After 3 hours and the passage of 2810 coulombs (i.e. 2.33 Faradays per mole of 6-bromoquinoline) the electrolysis was stopped.
  • the electrolysed solution plus dimethylformamide washings (20ml) from the electrochemical apparatus and the electrodes was treated with water (250ml) and then extracted three times with heptane (70ml), ethyl acetate (50ml) and diethyl ether (50ml). The combined extracts were evaporated under reduced pressure (2.7 kPa) at 40°C.
  • the residual yellow oil (2.78g) was subjected to Pressure Column Chromatography on silica [40 mm diameter column containing 100 g of silica 60 Merck (0,040-0,063 mm)] eluting with a mixture of cyclohexane, ethyl acetate and 2-propanol (90:8:2 then 85/12/3; v/v/v) under a slight pressure of argon (approximately 30 Kpa) to give the title compound (1.92g) as a yellowish oil.
  • the electrochemical apparatus is made up of: a cylindrical body (50ml volume) which contains the reaction medium and into which is plunged a 10 mm diameter soft iron bar (the consumable anode) and a cylindrical nickel foam grid (diameter 30mm, height 42.5mm, surfaces connect approximately 40ml) concentrically laid out around the anode; a glass lid provided with 5 threaded outputs; a central output for the electrical contact of the anode; four peripheral outputs for the electrical contact of the cathode, thermometer, tubing for argon arrival and a cooling agent with water.
  • the two parts of the electrolyser are associated by the intermediate of a 60 mm interior diameter flat grinding, ensuring the sealing.
  • the reaction medium is maintained under an inert atmosphere by continuously bubbling argon through the electrolysed solution.
  • the electrodes are connected to a stabilized power supply or an intentiostat.
  • a current integrator is connected in series.
  • the reaction medium is stirred by a Teflon ® covered magnet bar.
  • the body of the electrochemical apparatus can be plunged in an oil bath at the required temperature for the reaction.
  • 5-bromoindoline (10g) was added in one portion to molten Boc-anhydride (11.6g) at 30-40°C. Immediate effervescence was followed by the formation of a solid cake which was triturated with pentane to give the title compound (15g) as a white powder.
  • RAMOS cells (a pre-B cell line from ECACC, Porton Down, UK) are cultured in RPMI culture medium (Gibco, UK) supplemented with 5% foetal calf serum (FCS, Gibco, UK). Prior to assay the cells are suspended at a concentration of 0.5 X 10 6 cells/ml RPMI and labelled with 400 ⁇ Ci/100mls of [ 3 H]-methionine (Amersham, UK) for 18 hours at 37°C.
  • Cytostar plates (Amersham, UK) were coated with 50 ⁇ l/well of either 3 ⁇ g/ml human soluble VCAM-1 (R&D Systems Ltd, UK) or 28.8 ⁇ g/ml human tissue Fibronectin (Sigma, UK).
  • 50 ⁇ l phosphate buffered saline was added.
  • the plates were then left to dry in an incubator at 25°C, overnight.
  • the next day the plates were blocked with 200 ⁇ l/well of Pucks buffer (Gibco, UK) supplemented with 1% BSA (Sigma, UK).
  • the plates were left at room temperature in the dark for 2 hours.
  • the blocking buffer was then disposed of and the plates dried by inverting the plate and gently tapping it on a paper tissue.
  • the plates containing cells in control or compound test wells are incubated in the dark at room temperature for 1 hour.
  • the plates are then counted on a Wallac Microbeta scintillation counter (Wallac, UK) and the captured data processed in Microsoft Excel (Microsoft, US).
  • the data was expressed as an IC50, namely the concentration of inhibitor at which 50% of control binding occurs.
  • Compound data of this invention is expressed for IC 50 s for inhibition of cell adhesion to both fibronectin and VCAM-1.
  • Particular compounds of the invention inhibit cell adhesion to fibronectin and VCAM-1 with IC50s in the range 100 micromolar to 0.1 nanomolar.
  • Preferred compounds of the invention inhibit cell adhesion to fibronectin and VCAM-1 with IC50s in the range 10 nanomolar to 0.1 nanomolar.
  • Rats (Brown Norway, Harland Olac, UK) are sensitized on days 0, 12 and 21 with ovalbumin (100 ⁇ g, intraperitoneally [i.p], Sigma, UK) administered with aluminium hydroxide adjuvant (100mg, i.p., Sigma, UK) in saline (1ml, i.p.).
  • mice (C57) are sensitized on days 0 and 12 with ovalbumin (10 ⁇ g, i.p.) administered with aluminium hydroxide adjuvant (20mg, i.p.) in saline (0.2ml, i.p.).
  • Rats are challenged on any one day between days 28-38, while mice are challenged on any one day between days 20-30.
  • the animals are challenged by exposure for 30 minutes (rats) or 1 hour (mice) to an aerosol of ovalbumin (10g /1) generated by an ultrasonic nebulizer (deVilbiss Ultraneb, US) and passed into an exposure chamber.
  • an aerosol of ovalbumin (10g /1) generated by an ultrasonic nebulizer (deVilbiss Ultraneb, US) and passed into an exposure chamber.
  • aqueous-soluble compounds of this invention can be prepared in water (for oral, p.o. dosing) or saline (for intratracheal, i.t. dosing).
  • Non-soluble compounds are prepared as suspensions by grinding and sonicating the solid in 0.5 % methyl cellulose / 0.2 % polysorbate 80 in water (for p.o. dosing, both Merck UK Ltd., UK or saline (for i.t. dosing).
  • Dose volumes are: for rats 1ml /kg, p.o. or 0.5mg / kg, i.t.; for mice 10ml / kg, p.o. or 1ml / kg, i.t.
  • the cell accumulation in the lung is assessed 24 hours after challenge (rats) or 48-72 hours after challenge (mice).
  • the animals are euthanized with sodium pentobarbitone (200mg/kg, i.p., Pasteur Merieux, France) and the trachea is immediately cannulated.
  • Cells are recovered from the airway lumen by bronchoalveolar lavage (BAL) and from the lung tissue by enzymatic (collagenase, Sigma, UK) disaggregation as follows.
  • BAL is performed by flushing the airways with 2 aliquots (each 10 ml/kg) RPMI 1640 medium (Gibco, UK) containing 10 % fetal calf serum (FCS, Serotec Ltd., UK). The recovered BAL aliquots are pooled and cell counts made as described below.
  • RPMI 1640 / FCS RPMI 1640 / FCS
  • the lung lobes are removed and cut into 0.5 mm pieces.
  • Samples (rats: 400mg; mice: 150mg) of homogenous lung tissue are incubated in RPMI 1640 / FCS with collagenase (20 U/ml for 2 hours, then 60 U/ml for 1 hour, 37°C) to disaggregate cells from the tissue. Recovered cells are washed in RPMI 1640 / FCS.
  • Counts of total leukocytes recovered from the airway lumen and the lung tissue are made with an automated cell counter (Cobas Argos, US). Differential counts of eosinophils, neutrophils and mononuclear cells are made by light microscopy of cytocentrifuge preparations stained with Wright-Giemza stain (Sigma, UK). T cells are counted by flow cytometry (EPICS XL, Coulter Electronics, US) using fluophore-labelled antibodies against CD2 (a pan-T cell marker used to quantify total T cells), CD4, CD8 and CD25 (a marker of activated T cells). All antibodies were supplied by Serotec Ltd., UK).
  • the cell data was expressed as mean cell numbers in unchallenged, challenged and vehicle treated, and challenged and compound treated groups, including the standard error of the means.
  • Statistical analysis of the difference among treatment groups was evaluated using one-way analysis of variance via the Mann-Whitney test. Where p ⁇ 0.05 no statistical significance existed.

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Abstract

The invention is directed to physiologically active compounds of formula (I) wherein R1 represents R3-Z3-, R3-L2-R4-Z3-, R3-L3-Ar1-L4-Z3- or R3-L3-Ar1-L2-R4-Z3-; R2 represents hydrogen, halogen, lower alkyl or lower alkoxy; A1 represents a straight chain C1-3alkylene linkage optionally substituted by one or more groups chosen from alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, imino, oxo, thioxo, or alkyl substituted by -ZR6, -NY1Y2, -CO2R6 or -C(=O)-NY1Y2; L1 represents a direct bond; an alkenylene, alkylene, alkynylene, cycloalkenylene, cycloalkylene, heteroaryldiyl, heterocycloalkylene or arylene linkage each optionally substituted by (a) an acidic functional group, cyano, oxo, -S(O)mR9, R3, -C(=O)-R3, -C(=O)-OR3, -N(R8)-C(=O)R9, -N(R8)-SO2-R9, -NY4Y5 or -[C(=O)-N(R10)-C(R5)(R11)]p-C(=O)-NY4Y5, or by (b) alkyl substituted by an acidic functional group, or S(O)mR9, -C(=O)-NY4Y5 or -NY4Y5; a -[C(=O)-N(R10)-C(R5)(R11)]p- linkage; a -Z2-R12- linkage; a -C(=O)-CH2<

Description

  • This invention is directed to aza-bicycles, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states capable of being modulated by the inhibition of cell adhesion.
  • Cell adhesion is a process by which cells associate with each other, migrate towards a specific target or localise within the extra-cellular matrix. Many of the cell-cell and cell-extracellular matrix interactions are mediated by protein ligands (e.g. fibronectin, VCAM-1 and vitronectin) and their integrin receptors [e.g. α5β1 (VLA-5), α4β1 (VLA-4) and αVβ3]. Recent studies have shown these interactions to play an important part in many physiological (e.g. embryonic development and wound healing) and pathological conditions (e.g. tumour-cell invasion and metastasis, inflammation, atherosclerosis and autoimmune disease).
  • A wide variety of proteins serve as ligands for integrin receptors. In general, the proteins recognised by integrins fall into one of three classes: extracellular matrix proteins, plasma proteins and cell surface proteins. Extracellular matrix proteins such as collagen fibronectin, fibrinogen, laminin, thrombospondin and vitronectin bind to a number of integrins. Many of the adhesive proteins also circulate in plasma and bind to activated blood cells. Additional components in plasma that are ligands for integrins include fibrinogen and factor X. Cell bound complement C3bi and several transmembrane proteins, such as Ig-like cell adhesion molecule (ICAM-1,2,3) and vascular cell adhesion molecule (VCAM-1), which are members of the Ig superfamily, also serve as cell-surface ligands for some integrins.
  • Integrins are heterodimeric cell surface receptors consisting of two subunits called α and β. There are at least fifteen different α-subunits (α1-α9, α-L, α-M, α-X, α-IIb, α-V and α-E) and at least seven different β (β1-β7) subunits. The integrin family can be subdivided into classes based on the β subunits, which can be associated with one or more α-subunits. The most widely distributed integrins belong to the β1 class, also known as the very late antigens (VLA). The second class of integrins are leukocyte specific receptors and consist of one of three α-subunits (α-L, α-M or α-X) complexed with the β2 protein. The cytoadhesins α-IIbβ3 and α-Vβ3, constitute the third class of integrins.
  • The present invention principally relates to agents which modulate the interaction of the ligand VCAM-1 with its integrin receptor α4β1 (VLA-4), which is expressed on numerous hematopoietic cells and established cell lines, including hematopoietic precursors, peripheral and cytotoxic T lymphocytes, B lymphocytes, monocytes, thymocytes and eosinophils.
  • The integrin α4β1 mediates both cell-cell and cell-matrix interactions. Cells expressing α4β1 bind to the carboxy-terminal cell binding domain (CS-1) of the extracellular matrix protein fibronectin, to the cytokine-inducible endothelial cell surface protein VCAM-1, and to each other to promote homotypic aggregation. The expression of VCAM-1 by endothelial cells is upregulated by proinflammatory cytokines such as INF-γ, TNF-α, IL-1β and IL-4.
  • Regulation of α4β1 mediated cell adhesion is important in numerous physiological processes, including T-cell proliferation, B-cell localisation to germinal centres, and adhesion of activated T-cells and eosinophils to endothelial cells. Evidence for the involvement of VLA-4/VCAM-1 interaction in various disease processes such as melanoma cell division in metastasis, T-cell infiltration of synovial membranes in rheumatoid arthritis, autoimmune diabetes, collitis and leukocyte penetration of the blood-brain barrier in experimental autoimmune encephalomyelitis, atherosclerosis, peripheral vascular disease, cardiovascular disease and multiple sclerosis, has been accumulated by investigating the role of the peptide CS-1 (the variable region of fibronectin to which α4β1 binds via the sequence Leu-Asp-Val) and antibodies specific for VLA-4 or VCAM-1 in various in vitro and in vivo experimental models of inflammation. For example, in a Streptococcal cell wall-induced experimental model of arthritis in rats, intravenous administration of CS-1 at the initiation of arthritis suppresses both acute and chronic inflammation (S.M.Wahl et al., J.Clin.Invest., 1994,94, pages 655-662). In the oxazalone-sensitised model of inflammation (contact hypersensitivity response) in mice, intravenous administration of anti-α4 specific monoclonal antibodies significantly inhibited (50-60% reduction in the ear swelling response) the efferent response (P.L.Chisholm et al. J.Immunol., 1993, 23, pages 682-688). In a sheep model of allergic bronchoconstriction, HP1/2, an anti-α4 monoclonal antibody given intravenously or by aerosol, blocked the late response and the development of airway hyperresponsiveness (W.M. Abraham et al. J. Clin. Invest., 1994, 93 pages 776-787).
  • Bicyclic glycine derivatives of 7-aminodeacetoxycephalosporanic acid have been studied for use as orally adsorbable antibiotics (SJ Kukolja et al. J. Med. Chem., 1985,28, pages 1896-1903). Anticancer compositions are described in WO 9807716, having receptor specificity as well as activity in simulating formation of the enzyme transglutaminase as a marker for anticancer activity. The compositions comprise certain heteroarotinoid structures partially related to trans-retinoic acid through the basic, fused-ring framework. Indole and indoline derivatives are disclosed in EP 0042298 for use in the treatment of diabetes mellitus, hyperlipoproteinaemic states of atherosclerosis, and of associated disorders. Tetrahydro-6-quinolineacetic acid derivatives have been shown to have antirheumatic activity and suppressive effect on bone destruction (Kohno, Yasushi et al. Bioorg. Med. Chem. Lett., 1997,7, pages 1519-1524).
  • We have now found a novel group of aza-bicycles which have valuable pharmaceutical properties, in particular the ability to regulate the interaction of VCAM-1 and fibronectin with the integrin VLA-4 (α4β1).
  • Thus, in one aspect, the present invention is directed to aza-bicycles of general formula (I):-
    Figure imgb0001
     wherein:-
    • R1 represents:
      • (i) R3-Z3-;
      • (ii) R3-L2-R4-Z3-;
      • (iii) R3-L3-Ar1-L4-Z3-; or
      • (iv) R3-L3-Ar1-L2-R4-Z3-;
    • R2 represents hydrogen, halogen, C1-4alkyl or C1-4alkoxy;
    • R3 represents alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocycloalkyl or heterocycloalkylalkyl;
    • R4 represents an alkylene chain, an alkenylene chain, or an alkynylene chain;
    • R5 represents hydrogen or C1-4alkyl;
    • R6 represents hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl or heteroarylalkyl;
    • R7 and R7a are each independently hydrogen or C1-4alkyl;
    • R8 represents hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
    • R9 represents alkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, or alkyl substituted by aryl, an acidic functional group, cycloalkyl, heteroaryl, heterocycloalkyl, -S(O)mR3, -C(=O)-NY4Y5 or -NY4Y5;
    • R10 represents hydrogen, R3 or alkyl substituted with alkoxy, cycloalkyl, hydroxy, mercapto, alkylthio or -NY4Y5;
    • R11 and R13 are each independently selected from hydrogen or a group consisting amino acid side chains, an acidic functional group, R3, -C(=O)-R3, or -C(=O)-NY4Y5, or alkyl substituted by an acidic functional group or by R3, -NY4Y5, -NH-C(=O)-R3, -C(=O)-R4-NH2, -C(=O)-Ar1-NH2, -C(=O)-R4-CO2H, or -C(=O)-NY4Y5;
    • or R10 and R11 or R10 and R12 together with the atoms to which they attached form a 3- to 6-membered heterocycloalkyl ring;
    • R12 represents C1-6alkylene, optionally substituted by R3;
    • R14 represents alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
    • A1 represents a straight chain C1-2alkylene linkage optionally substituted by one or more groups chosen from alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, imino, oxo, thioxo, or alkyl substituted by -ZR6, -NY1Y2, -CO2R6 or -C(=O)-NY1Y2;
    • Ar1 represents arylene or heteroaryldiyl;
    • L1 represents:
      • (i) a direct bond;
      • (ii) an alkenylene, alkylene, alkynylene, cycloalkenylene, cycloalkylene, heteroaryldiyl, heterocycloalkylene or arylene linkage each optionally substituted by (a) an acidic functional group, cyano, oxo, -S(O)mR9, R3, -C(=O)-R3, -C(=O)-OR3, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9, -NY4Y5 or -[C(=O)-N(R10)-C(R5)(R11)]p-C(=O)-NY4Y5, or by (b) alkyl substituted by an acidic functional group, or by S(O)mR9, -C(=O)-NY4Y5 or -NY4Y5;
      • (iii) a -[C(=O)-N(R10)-C(R5)(R11)]p- linkage;
      • (iv) a -Z2-R12- linkage;
      • (v) a -C(=O)-CH2-C(=O)- linkage;
      • (vi) a -R12-Z2-R12- linkage;
      • (vii) a -C(R4)(R13)-[C(=O)-N(R10)-C(R5)(R11)]p- linkage; or
      • (viii) a -L5-L6-L7- linkage;
    • L2 represents a -NR5-C(=Z)-NR5-, -C(=Z)-NR5-, -C(=O)-, -C(=Z)-O-, -NR5-C(=Z)-, -Z-, -S(O)m-, -NR5-, -SO2-NR5-, -NR5-SO2-, -NR5-C(=O)-O-, -O-C(=O)-, or -O-C(=O)-NR5- linkage;
    • L3 represents a heteroaryldiyl, -NR5-C(=Z)-NR5-, -C(=Z)-NR5-, -C(=Z)-O-, -NR5-C(=Z)-, -Z-, -S(O)m-, -NR5-, -SO2-NR5-, -NR5-SO2-, -NR5-C(=O)-O-, -O-C(=O)-, or -O-C(=O)-NR5-linkage;
    • L4 represents a direct bond, an alkylene, alkenylene or alkynylene chain;
    • L5 and L7 each independently represent a direct bond or an alkylene chain;
    • L6 represents a cycloalkylene or heterocycloalkylene linkage;
    • Y1 and Y2 are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group -NY1Y2 may form a cyclic amine;
    • Y4 and Y5 are independently hydrogen, alkenyl, alkyl, alkynyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, heterocycloalkyl, or alkyl substituted by alkoxy, aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl, hydroxy, oxo, -NY1Y2, or one or more -CO2R8 or -C(=O)-NY1Y2 groups; or the group -NY4Y5 may form a 5- to 7-membered cyclic amine which (i) may be optionally substituted with one or more substituents selected from alkoxy, carboxamido, carboxy, hydroxy, oxo (or a 5-, 6- or 7-membered cyclic acetal derivative thereof), R10; (ii) may also contain a further heteroatom selected from O, S, SO2, or NY6; and (iii) may also be fused to additional aryl, heteroaryl, heterocycloalkyl or cycloalkyl rings to form a bicyclic or tricyclic ring system;
    • Y6 represents hydrogen, alkyl, aryl, arylalkyl, -C(=O)-R14, -C(=O)-OR14 or -SO2R14;
    • Z is an oxygen or sulphur atom;
    • Z1 is C(R7)(R7a), C(=O) or CH(OH);
    • Z2 is O, S(O)n, NR5, SONR5, C(=O)NR5 or C(=O);
    • Z3 is C(=O);
    • m is an integer 1 or 2; n is zero or an integer 1 or 2;
    • p is zero or an integer 1 to 4; and
    • Y is carboxy;
    and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs, but excluding compounds where an oxygen, nitrogen or sulphur atom is attached directly to a carbon carbon multiple bond of an alkenylene, alkynylene or cycloalkenylene residue, and excluding N-acetylindoline-5-glycine;
    and wherein said acidic functional group is selected from the group consisting of carboxyl, hydroxyl, mercapto and imidazole.
  • In the present specification, the term "compounds of the invention", and equivalent expressions, are meant to embrace compounds of general formula (I) as hereinbefore described, which expression includes the ester prodrugs, protected derivatives of compounds of formula (I) containing one or more acidic functional groups and/or amino-acid side chains, the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, where the context so permits.
    Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits.
  • As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:-
  • "Patient" includes both human and other mammals.
  • "Acid bioisostere" means a group which has chemical and physical similarities producing broadly similar biological properties to a carboxy group (see Lipinski, Annual Reports in Medicinal Chemistry, 1986,21,p283 "Bioisosterism In Drug Design"; Yun, Hwahak Sekye, 1993,33,p576-579 "Application Of Bioisosterism To New Drug Design"; Zhao, Huaxue Tongbao, 1995,p34-38 "Bioisosteric Replacement And Development Of Lead Compounds In Drug Design"; Graham, Theochem, 1995,343,p105-109 "Theoretical Studies Applied To Drug Design:ab initio Electronic Distributions In Bioisosteres"). Examples of suitable acid bioisosteres include: -C(=O)-NHOH, -C(=O)-CH2OH, -C(=O)-CH2SH, -C(=O)-NH-CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, heteroarylsulphonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or heterocyclic phenols such as 3-hydroxyisoxazolyl and 3-hydoxy-1-methylpyrazolyl.
  • "Acidic functional group" means a group with an acidic hydrogen within it. The "protected derivatives" are those where the acidic hydrogen atom has been replaced with a suitable protecting group. For suitable protecting groups see T.W. Greene and P.G.M.Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991. Exemplary acidic functional groups include carboxyl (and acid bioisosteres), hydroxy, mercapto and imidazole. Exemplary protected derivatives include esters of carboxy groups (i.e. -CO2R14), ethers of hydroxy groups (i.e. -OR14), thioethers of mercapto groups (i.e. -SR14), and N-benzyl derivatives of imidazoles.
  • "Acyl" means an H-CO- or alkyl-CO- group in which the alkyl group is as described herein.
  • "Acylamino" is an acyl-NH- group wherein acyl is as defined herein.
  • "Alkenyl" means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. "Branched", as used herein and throughout the text, means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear chain; here a linear alkenyl chain. "Lower alkenyl" means about 2 to about 4 carbon atoms in the chain which may be straight or branched. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.
  • "Alkenylene" means an aliphatic bivalent radical derived from a straight or branched alkenyl group, in which the alkenyl group is as described herein. Exemplary alkenylene radicals include vinylene and propylene.
  • "Alkoxy" means an alkyl-O- group in which the alkyl group is as described herein. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.
  • "Alkoxycarbonyl" means an alkyl-O-CO- group in which the alkyl group is as described herein. Exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.
  • "Alkyl" means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 15 carbon atoms in the chain. Particular alkyl groups have from 1 to about 6 carbon atoms. "Lower alkyl" as a group or part of a lower alkoxy, lower alkylthio, lower alkylsulphinyl or lower alkylsulphonyl group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 4 carbon atoms in the chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl.
  • "Alkylene" means an aliphatic bivalent radical derived from a straight or branched C1-6alkyl group, in which the alkyl group is as described herein. Exemplary alkylene radicals include methylene, ethylene and trimethylene.
  • "Alkylenedioxy" means an -O-alkyl-O- group in which the alkyl group is as defined above. Exemplary alkylenedioxy groups include methylenedioxy and ethylenedioxy.
  • "Alkylsulphinyl" means an alkyl-SO- group in which the alkyl group is as previously described. Preferred alkylsulphinyl groups are those in which the alkyl group is C1-4alkyl.
  • "Alkylsulphonyl" means an alkyl-SO2- group in which the alkyl group is as previously described. Preferred alkylsulphonyl groups are those in which the alkyl group is C1-4alkyl.
  • "Alkylsulphonylcarbamoyl" means an alkyl-SO2-NH-C(=O)- group in which the alkyl group is as previously described. Preferred alkylsulphonylcarbamoyl groups are those in which the alkyl group is C1-4alkyl.
  • "Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Exemplary alkylthio groups include methylthio, ethylthio, isopropylthio and heptylthio.
  • "Alkynyl" means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, i-butynyl, 3-methylbut-2-ynyl, and n-pentynyl.
  • "Alkynylene" means an aliphatic bivalent radical derived from a C2-6alkynyl group. Exemplary alkynylene radicals include ethynylene and propynylene.
  • "Amino acid side chains" means the substituent found on the carbon between the amino and carboxy groups in α-amino acids. For examples of "protected derivatives" of amino acid side chains, see T.W. Greene and P.G.M.Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.
  • "Aroyl" means an aryl-CO- group in which the aryl group is as described herein. Exemplary aroyl groups include benzoyl and 1- and 2-naphthoyl.
  • "Aroylamino" is an aroyl-NH- group wherein aroyl is as previously defined.
  • "Aryl" as a group or part of a group denotes: (i) a monocyclic or multicyclic aromatic carbocyclic moiety of about 6 to about 14 carbon atoms, such as phenyl or naphthyl; or (ii) a partially saturated multicyclic aromatic carbocyclic moiety in which an aryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure, such as a tetrahydronaphthyl, indenyl or indanyl ring. Aryl groups may be substituted with one or more aryl group substituents which may be the same or different, where "aryl group substituent" includes, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulphinyl, alkylsulphonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulphinyl, arylsulphonyl, arylthio, carboxy, cyano, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, hydroxy, nitro, trifluoromethyl, Y1Y2N-, Y1Y2NCO-, Y1Y2NSO2-, Y1Y2N-C2-6alkylene-Z4- {where Z4 is O, NR6 or S(O)n}, alkylC(=O)-Y1N-, alkylSO2-Y1N- or alkyl optionally substituted with aryl, heteroaryl, hydroxy, or Y1Y2N-.
  • "Arylalkenyl" means an aryl-alkenyl- group in which the aryl and alkenyl are as previously described. Preferred arylalkenyls contain a lower alkenyl moiety. Exemplary arylalkenyl groups include styryl and phenylallyl.
  • "Arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C1-4alkyl moiety. Exemplary arylalkyl groups include benzyl, 2-phenethyl and naphthlenemethyl.
  • "Arylalkyloxy" means an arylalkyl-O- group in which the arylalkyl groups is as previously described. Exemplary arylalkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
  • "Arylalkyloxycarbonyl" means an arylalkyl-O-CO- group in which the arylalkyl groups is as previously described. An exemplary arylalkyloxycarbonyl group is benzyloxycarbonyl.
  • "Arylalkylthio" means an arylalkyl-S- group in which the arylalkyl group is as previously described. An exemplary arylalkylthio group is benzylthio.
  • "Arylalkynyl" means an aryl-alkynyl- group in which the aryl and alkynyl are as previously described. Exemplary arylalkynyl groups include phenylethynyl and 3-phenylbut-2-ynyl.
  • "Arylene" means a bivalent radical derived from an aryl group. Exemplary arylene groups include phenylene, naphthylene and indanylene. When Ar1 is arylene this may particularly represent a phenylene.
  • "Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Exemplary aryloxy groups include phenoxy and naphthoxy.
  • "Aryloxycarbonyl" means an aryl-O-C(=O)- group in which the aryl group is as previously described. Exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
  • "Arylsulphinyl" means an aryl-SO- group in which the aryl group is as previously described.
  • "Arylsulphonyl" means an aryl-SO2- group in which the aryl group is as previously described.
  • "Arylsulphonylcarbamoyl" means an aryl-SO2-NH-C(=O)- group in which the aryl group is as previously described.
  • "Arylthio" means an aryl-S- group in which the aryl group is as previously described. Exemplary arylthio groups include phenylthio and naphthylthio.
  • "Azaheteroaryl" means an aromatic carbocyclic moiety of about 5 to about 10 ring members in which one of the ring members is nitrogen and the other ring members are chosen from carbon, oxygen, sulphur, or nitrogen. Examples of azaheteroaryl groups include pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, imidazolyl, and benzimidazolyl.
  • "Azaheteroaryldiyl" means a bivalent radical derived from a heteroaryl group.
  • "Cyclic amine" means a 3 to 8 membered monocyclic cycloalkyl ring system where one of the ring carbon atoms is replaced by nitrogen and which (i) may optionally contain an additional heteroatom selected from O, S or NY3 (where Y3 is hydrogen, alkyl, arylalkyl, and aryl) and (ii) may be fused to additional aryl or heteroaryl ring to form a bicyclic ring system. Exemplary cyclic amines include pyrrolidine, piperidine, morpholine, piperazine, indoline and pyrindoline.
  • "Cycloalkenyl" means a non-aromatic monocyclic or multicyctic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • "Cycloalkenylalkyl" means a cycloalkenyl-alkyl- group in which the cycloalkenyl and alkyl moieties are as previously described. Exemplary cycloalkenylalkyl groups include cyclopentenylmethyl, cyclohexenylmethyl or cycloheptenylmethyl.
  • "Cycloalkenylene" means a bivalent radical derived from an unsaturated monocyclic hydrocarbon of about 3 to about 10 carbon atoms by removing a hydrogen atom from each of two different carbon atoms of the ring. Exemplary cycloalkenylene radicals include cyclopentenylene and cyclohexenylene.
  • "Cycloalkyl" means a saturated monocyclic or bicyclic ring system of about 3 to about 10 carbon atoms optionally substituted by oxo. Exemplary monocyclic cycloalkyl rings include C3-8cycloalkyl rings such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • "Cydoalkylalkenyl" means a cycloalkyl-alkenyl- group in which the cycloalkyl and alkenyl moieties are as previously described. Exemplary monocyclic cycloalkylalkenyl groups include cyclopentylvinylene and cyclohexylvinylene.
  • "Cycloalkylalkyl" means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as previously described. Exemplary monocyclic cycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
  • "Cycloalkylalkynyl" means a cycloalkyl-alkynyl- group in which the cycloalkyl and alkynyl moieties are as previously described. Exemplary monocyclic cycloalkylalkynyl groups include cyclopropylethynyl, cyclopentylethynyl and cyclohexylethynyl.
  • "Cycloalkylene" means a bivalent radical derived from a saturated monocyclic hydrocarbon of about 3 to about 10 carbon atoms by removing a hydrogen atom from each of two different carbon atoms of the ring. Exemplary cycloalkenylene radicals include cyclopentylene and cyclohexylene.
  • "Halo" or "halogen" means fluoro, chloro, bromo, or iodo. Preferred are fluoro or chloro.
  • "Heteroaroyl" means a heteroaryl-C(=O)- group in which the heteroaryl group is as described herein. Exemplary groups include pyridylcarbonyl.
  • "Heteroaroylamino" means a heteroaroyl-NH- group in which the heteroaryl moiety are as previously described.
  • "Heteroaryl" as a group or part of a group denotes: (i) a aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulphur (examples of such groups include benzimidazolyl, benzthiazolyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups, optionally substituted by one or more aryl group substituents as defined above); (ii) a partially saturated multicyclic heterocarbocyclic moiety in which a heteroaryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure (examples of such groups include pyrindanyl groups). When R1 or L1 contains a heteroaryl group this may particularly represent a "azaheteroaryl" group.
  • "Heteroarylalkenyl" means a heteroaryl-alkenyl- group in which the heteroaryl and alkenyl moieties are as previously described. Preferred heteroarylalkenyl groups contain a lower alkenyl moiety. Exemplary heteroarylalkenyl groups include pyridylethenyl and pyridylallyl.
  • "Heteroarylalkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a C1-4alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.
  • "Heteroarylalkyloxy" means an heteroarylalkyl-O- group in which the heteroarylalkyl group is as previously described. Exemplary heteroaryloxy groups include pyridylmethoxy.
  • "Heteroarylalkynyl" means a heteroaryl-alkynyl- group in which the heteroaryl and alkynyl moieties are as previously described. Exemplary heteroarylalkenyl groups include pyridylethynyl and 3-pyridylbut-2-ynyl.
  • "Heteroaryldiyl" means a bivalent radical derived from an aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulphur. When Ar1 is a heteroaryldiyl group this may particularly represent an "azaheteroaryldiyl" group.
  • "Heteroaryloxy" means an heteroaryl-O- group in which the heteroaryl group is as previously described. Exemplary heteroaryloxy groups include pyridyloxy.
  • "Heteroarylsulphonylcarbamoyl" means a heteroaryl-SO2-NH-C(=O)- group in which the heteroaryl group is as previously described.
  • "Heterocycloalkyl" means: (i) a cycloalkyl group of about 3 to 7 ring members which contains one or more heteroatoms selected from O, S or NY3; (ii) a partially saturated multicyclic heterocarbocyclic moiety in which an aryl (or heteroaryl ring) and a heterocycloalkyl group are fused together to form a cyclic structure (examples of such groups include chromanyl, dihydrobenzofuranyl, indolinyl and pyrindolinyl groups).
  • "Heterocycloalkylalkyl" means a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as previously described.
  • "Heterocycloalkylene" means a bivalent radical derived from a saturated monocyclic hydrocarbon of about 5 to about 7 atoms, which contains one or more heteroatoms selected from O, S or NY3. Such a radical may be substituted by oxo, by removing a hydrogen atom from each of two different carbon atoms of the ring, or when NY3 is NH by removing a hydrogen atom from one carbon atom of the ring and a hydrogen atom from the NH, or when the ring contains two NY3 heteroatoms and NY3 is NH by removing a hydrogen atom from both nitrogen atoms. When L1 is a heterocycloalkylene group this may particularly represent a bivalent radical derived pyrrolidine, especially 3,4-pyrrolidinediyl.
  • "Prodrug" means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of formula (I), including N-oxides thereof. For example an ester of a compound of formula (I) containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule. Alternatively an ester of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • Suitable esters of compounds of formula (I) containing a hydroxy group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-β-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
  • Suitable esters of compounds of formula (I) containing a carboxy group, are for example those described by F.J.Leinweber, Drug Metab. Res., 1987,18, page 379.
  • Suitable esters of compounds of formula (I) containing both a carboxy group and a hydroxy group within the moiety -L1-Y, include lactones, formed by loss of water between said carboxy and hydroxy groups. Examples of lactones include caprolactones and butyrolactones.
  • An especially useful class of esters of compounds of formula (I) containing a hydroxy group, may be formed from acid moieties selected from those described by Bundgaard et. al., J. Med. Chem., 1989, 32 , page 2503-2507, and include substituted (aminomethyl)-benzoates, for example dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, more especially (morpholino-methyl)benzoates, e.g. 3- or 4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-1-yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-1-yl)benzoates.
  • Where the compound of the invention contains a carboxy group, or a sufficiently acidic bioisostere, base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form. The bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the cations. Pharmaceutically acceptable salts, including those derived from alkali and alkaline earth metal salts, within the scope of the invention include those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, and the like.
  • Some of the compounds of the present invention are basic, and such compounds are useful in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt thereof.
  • Acid addition salts are a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form. The acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts within the scope of the invention include those derived from mineral acids and organic acids, and include hydrohalides, e.g. hydrochlorides and hydrobromides, sulphates, phosphates, nitrates, sulphamates, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methane-sulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
  • As well as being useful in themselves as active compounds, salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.
  • With reference to formula (I) above, the following are particular and preferred groupings:
  • R1 may particularly represent a group R3-Z3- in which Z3 is C(=O), and R3 is as defined above, especially (i) aryl, such as optionally substituted phenyl [preferred optional substituents include aryloxy, cyano, halo (e.g. chloro or fluoro), lower alkoxy (e.g. methoxy), lower alkyl (e.g. methyl), nitro and perfluoroloweralkyl (e.g. trifluoromethyl)], (ii) heteroaryl, such as isoquinolinyl, isoxazolyl, pyrazolopyrimidinyl, pyridyl, pyrimidinyl quinolinyl, thiazolyl and triazolyl, each optionally substituted by one or more aryl group substituents as described hereinbefore [preferred optional substituents include alkyl-C(=O)-, aryl, cyano, halo, (e.g. chloro or fluoro), lower alkoxy (e.g. methoxy), lower alkyl (e.g. methyl), lower alkylsulphonyl, lower alkylthio, nitro and perfluoroloweralkyl (e.g. trifluoromethyl)] or (iii) arylalkyl in which the aryl group is optionally substituted by one, or preferably two aryl group substituents (preferred optional substituents include halo, hydroxy and methoxy). R1 may particularly represent a group R3-C(=O)- in which R3 is a substituted aryl selected from 2-chlorophenyl, 5-chloro-2-cyanophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 4-fluoro-2-trifluoromethyl, 2-methyl-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2-nitrophenyl, 3-nitrophenyl, 2-phenoxyphenyl or a heteroaryl selected from quinolin-4-yl, isoquinolin-2-yl, 2,4-pyridin-3-yl, 2,6-dimethyl-4-trifluoromethylpyridin-3-yl, 4-trifluoromethylpyridin3-yl, 2-phenyl-4-methyl-1,2,3-triazol-5-yl, 3,5-dimethylisoxazol-4-yl, 2,7-dimethylpyraxolo-[1,5-a]pyrimidin-6-yl, 2-isopropyl-4-methylthiazol-5-yl, 4-trifluoromethylpyrimidin-5-yl, 4-hydroxybenzyl, 3-chloro-4-hydroxybenzyl, 3-fluoro-4-hydroxybenzyl, and 4-hydroxy-3-methoxybenzyl.
  • R1 may also particularly represent a group R3-L3-Ar1-L4-Z3- in which Z3 is C(=O); L4 represents a straight or branched C1-6alkylene chain, more particularly a straight C1-4alkylene chain such as methylene or ethylene, preferably methylene; Ar1 is an optionally substituted phenylene, such as optionally substituted m- or p-phenylene, preferably optionally substituted p-phenylene, more preferably a 3-substituted p-phenylene, in which the substituent is ortho to the R3-L3- group, (preferred optional substituents include halo, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, C1-4alkylsulphinyl and C1-4alkylsulphonyl, especially chloro, methyl, methoxy, methylthio, methylsulphinyl and methylsulphonyl), or Ar1 is an heteroaryldiyl, such as azaheteroaryldiyl, (e.g. optionally substituted pyridinediyl, preferably a p-pyridinediyl), where the optional substituents include C1-4alkyl and C1-4alkoxy, especially methyl and methoxy, more preferably a pyridine-2,5-diyl, in which the R3-L3- group is adjacent to the pyridyl nitrogen atom, and which is substituted in the 4- or 6-position with a methyl or methoxy group; L3 represents a -NH-C(=O)-NH- linkage; and R3 is as defined above, particularly an aryl group (such as optionally substituted phenyl) or an heteroaryl (such as optionally substituted pyridyl), and is preferably 2- or 3-methyl(or methoxy)phenyl, more preferably 2-methylphenyl, or 3-methyl-2-pyridyl.
  • R1 may also particularly represent a group R3-L3-Ar1-L4-Z3- in which: Z3 is C(=O); L4 represents a straight or branched C1-6alkylene chain, more particularly a straight C1-4alkylene chain such as methylene or ethylene, preferably methylene; Ar1 is an 8 to 10 membered bicyclic system
    Figure imgb0002
     in which (i) ring
    Figure imgb0003
     is a 5 or 6 membered optionally substituted heterocycle, preferably a 5 membered heteroaryl ring, (ii) ring
    Figure imgb0004
     is a 5 or 6 membered optionally substituted heterocycle or an optionally substituted benzene ring, preferably a benzene ring, (iii) each ring is optionally substituted by one or more "aryl group substituents" as defined above, (iv) the two rings are joined together by a carbon-carbon linkage or a carbon-nitrogen linkage, and
    Figure imgb0005
     is preferably optionally substituted benzoxazolyl or optionally substituted benzimidazolyl, each [more particularly ring
    Figure imgb0006
     optionally substituted by one or more "aryl group substituents" as defined above [examples of particular aryl group substituents include lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy), amino, halogen, hydroxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, nitro or trifluoromethyl]; L3 represents NR5, especially NH; and R3 is as defined above, particularly aryl, such as a 2-substituted phenyl, [examples of particular aryl group substituents include lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy), halo (e.g. fluoro or chloro) and Y1Y2N-(e.g. dimethylamino)], and is preferably 2-methylphenyl.
  • R1 may also particularly represent a group R3-L3-Ar1-L4-Z3- in which: Z3 is C(=O); L4 represents a straight or branched C1-6alkylene chain, more particularly a straight C1-4alkylene chain such as methylene or ethylene, preferably methylene; Ar1 is an optionally substituted phenylene, such as optionally substituted m- or p-phenylene, preferably optionally substituted p-phenylene, more preferably a 3-substituted p-phenylene, in which the substituent is ortho to the R3-L3- group, (preferred optional substituents include chloro, C1-4alkyl, C1-4alkoxy, C1-4allrylthio, C1-4alkylsulphinyl and C1-4alkylsulphonyl, especially chloro, methyl, methoxy, methylthio, methylsulphinyl and methylsulphonyl), or Ar1 is an heteroaryldiyl, such as azaheteroaryldiyl, (e.g. optionally substituted pyridinediyl, preferably a p-pyridinediyl), where the optional substituents include C1-4alkyl and C1-4alkoxy, especially methyl and methoxy, more preferably a pyridine-2,5-diyl, in which the R3-L3- group is adjacent to the pyridyl nitrogen atom, and which is substituted in the 4- or 6-position with a methyl or methoxy group; L3 represents -C(=O)-NH- and R3 is heterocycloalkyl, more particularly a bicyclic amine containing 9-10 atoms, especially indolinyl.
  • R2 may particularly represent hydrogen.
  • R2 may also particularly represent lower alkyl, (e.g. methyl).
  • R2 may also particularly represent lower alkoxy (e.g. methoxy).
  • A1 may particularly represent an unsubstituted straight chain C1-2alkylene linkage, i.e. methylene or ethylene.
  • Z1 may particularly represent C(R7)(R7a), especially where R7 and R7a are both hydrogen.
  • L1 may particularly represent an optionally substituted alkylene linkage, especially optionally substituted ethylene or propylene, preferably optionally substituted ethylene. Preferred optional substituents include lower alkyl, aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9, -NY4Y5 and -[C(=O)-N(R10)-C(R5)(R11)]p-C(=O)-NY4Y5 or alkyl substituted by carboxy, -ZH, -ZR3, -C(=O)-NY4Y5 or -NY4Y5. In one preferred embodiment L1 is a group
    Figure imgb0007
     [where R5 is hydrogen or lower alkyl (e.g. methyl) and R15 represents hydrogen or lower alkyl, or where R5 is hydrogen and R15 represents aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9, -NY4Y5 or -[C(=O)-N(R10)-C(R5)(R11)]p-C(=O)-NY4Y5, or alkyl substituted by carboxy, -ZH, -ZR3, -C(=O)-NY4Y5 or -NY4Y5], and is more preferably a group
    Figure imgb0008
     particularly
    Figure imgb0009
     [where R15 represents hydrogen, lower alkyl, aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9 or -NY4Y5 or alkyl substituted by carboxy, -OH, -OR3 or -C(=O)-NY4Y5]. In another preferred embodiment L1 is a group
    Figure imgb0010
     [where R5 is hydrogen or lower alkyl (e.g. methyl) and R15a represents lower alkyl, or where R5 is hydrogen and R15a represents aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9, -NY4Y5 or -[C(=O)-N(R10)-C(R5)(R11)]p-C(=O)-NY4Y5, or alkyl substituted by carboxy, -ZH, -ZR3, -C(=O)-NY4Y5 or -NY4Y5], and is more preferably a group
    Figure imgb0011
     particularly
    Figure imgb0012
     [where R15a represents -N(R8)-C(=O)-R9, or -N(R8)-SO2-R9].
  • L1 may also particularly represent an unsubstituted alkenylene linkage, especially vinylene.
  • L1 may also particularly represent a -Z2-R12- linkage, such as -O-CH2-, -S(O)n-CH2-, -S(O)n-CH2-CH2-, or especially -NH-CH2-.
  • L1 may also particularly represent a -L5-L6-L7- linkage, in which (i) L5 and L7 are both a direct bond and L6 is heterocycloalkylene, such as pyrrolidindiyl, especially 3,4-pyrrolidindiyl, or cycloalkylene, such as cyclopentyl, (ii) L5 is alkylene, such as methylene, L6 is cycloalkylene, such as cyclopentyl, and L7 is a direct bond, or (iii) L5 is a direct bond, L6 is cycloalkylene, such as cyclopentyl, and L7 is alkylene, such as methylene.
  • It is to be understood that this invention covers all appropriate combinations of the particular and preferred groupings referred to herein.
  • A particular group of compounds of the invention are compounds of formula (Ix):-
    Figure imgb0013
     wherein:-
    • R1 represents a group selected from :
      • (i) R3-
      • (ii) R3-L2-R4-
      • (iii) R3-L3-Ar1-L4-
      • (iv) R3-L3-Ar1-L2-R4-
      [where:
    • R3 is alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocycloalkyl or heterocycloalkylalkyl;
    • L2 represents a -NR5-C(=Z)-NR5-, -C(=Z)-NR5-, -C(=O)-, -C(=Z)-O-, -NR5-C(=Z)-, -Z-, -SO-, -SO2-, -NR5-, -SO2-NR5-, -NR5-SO2-, -NR5-C(=O)-O-, -O-C(=O)-, or -O-C(=O)-NR5- linkage;
    • L3 represents a heteroaryldiyl, heterocycloalkylene, -NR5-C(=Z)-NR5-, -C(=Z)-NR5-, -C(=Z)-O-, -NR5-C(=Z)-, -Z-, -SO-, -SO2-, -NR5-, -SO2-NR5-, -NR5-SO2-, -NR5-C(=O)-O-, -O-C(=O)-, or -O-C(=O)-NR5- linkage;
    • L4 is a direct bond, an alkylene, alkenylene or alkynylene chain, or a -L5-NR5- linkage;
    • L5 is a direct bond or an alkylene chain;
    • R4 is an alkylene chain, an alkenylene chain, or an alkynylene chain;
    • R5 is hydrogen or lower alkyl;
    • Ar1 is phenylene or heteroaryldiyl; and
    • Z represents an oxygen or sulphur atom;
    • but excluding compounds where an oxygen, nitrogen or sulphur atom is attached directly to a carbon carbon multiple bond of an alkenylene or alkynylene residue];
    • R2 represents hydrogen, halogen, lower alkyl or lower alkoxy;
    • A1 represents a straight chain C1-2alkylene linkage optionally substituted by one or more groups chosen from alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, imino, oxo, thioxo, or alkyl substituted by -ZR6, -NY1Y2, -CO2R6 or -C(=O)-NY1Y2 [where: R6 is hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl or heteroarylalkyl; and Y1 and Y2 are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group -NY1Y2 may form a heterocycloalkyl group] ;
    • Z1 represents C(R7)(R7a) or C(=O) {where R7 and R7a are each independently hydrogen or lower alkyl};
    • L1 represents:
      • (i) a direct bond;
      • (ii) an alkenylene, alkylene, alkynylene, cycloalkenylene, cycloalkylene, heteroaryldiyl, heterocycloalkylene or arylene linkage each optionally substituted by (a) an acidic functional group (or corresponding protected derivative), R3, -C(=O)-R3, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9, -[C(=O)-N(R10)-C(R5)(R11)]p-C(=O)-NY4Y5 or-NY4Y5, or by (b) alkyl substituted by an acidic functional group (or corresponding protected derivative), or by -C(=O)-NY4Y5 or -NY4Y5;
      • (iii) a -[C(=O)-N(R10)-C(R5)(R11)]p- linkage;
      • (iv) a -Z2-R12- linkage;
      • (v) a -C(=O)-CH2-C(=O)- linkage;
      • (vi) a -R12-Z2-R12- linkage; or
      • (vii) a -C(R4)(R13)-[C(=O)-N(R10)-C(R5)(R11)]p-linkage;
      {in which
    • R8 is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
    • R9 is alkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, or alkyl substituted by aryl, an acidic functional group (or corresponding protected derivative), cycloalkyl, heteroaryl, heterocycloalkyl, -ZH, -ZR3, -C(=O)-NY4Y5 or -NY4Y5;
    • R10 is hydrogen, R3 or alkyl substituted with alkoxy, cycloalkyl, hydroxy, mercapto, alkylthio or -NY4Y5;
    • R11 and R13 are each independently selected from hydrogen or a group consisting amino acid side chains and corresponding protected derivatives, an acidic functional group (or corresponding protected derivative), R3, -C(=O)-R3, or -C(=O)-NY4Y5, or alkyl substituted by an acidic functional group (or corresponding protected derivative) or by R3, -NY4Y5, -NH-C(=O)-R3, -C(=O)-R4-NH2, -C(=O)-Ar1-NH2, -C(=O)-R4-CO2H, or -C(=O)-NY4Y5; or R10 and R11 or R10 and R12 together with the atoms to which they attached form a 3- to 6-membered heterocycloalkyl ring;
    • R12 is C1-6alkylene, optionally substituted by R3;
    • Y4 and Y5 are independently hydrogen, alkenyl, alkyl, alkynyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, heterocycloalkyl, or alkyl substituted by alkoxy, aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl, hydroxy, oxo, -NY1Y2, or one or more -CO2R7 or -C(=O)-NY1Y2 groups; or the group -NY4Y5 may form a 5- to 7-membered cyclic amine which (i) may be optionally substituted with one or more substituents selected from alkoxy, carboxamido, carboxy, hydroxy, oxo (or a 5-, 6- or 7-membered cyclic acetal derivative thereof), R10; (ii) may also contain a further heteroatom selected from O, S, SO2, or NY6 [where Y6 is hydrogen, alkyl, aryl, arylalkyl, -C(=O)-R14, -C(=O)-OR14 or -SO2R14 (in which R14 is alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl)]; and (iii) may also be fused to additional aryl, heteroaryl, heterocycloalkyl or cycloalkyl rings to form a bicyclic or tricyclic ring system;
    • Z2 is O, S(O)n, NR5, SONR5, C(=O)NR5 or C(=O); and
    • p is zero or an integer 1 to 4}; and
    • Y is carboxy;
    and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  • Another particular group of compounds of the invention are compounds of formula (Ia):-
    Figure imgb0014
     in which R2, R3, A1, Ar1, L1, L4, Y and Z1 are as hereinbefore defined, and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  • Compounds of formula (Ia) in which R3 represents an aryl group, particularly an optionally substituted phenyl group, such as a 2-substituted phenyl, especially 2-methylphenyl, are preferred.
  • Compounds of formula (Ia) in which R3 represents an heteroaryl group, particularly an optionally substituted pyridyl, such as optionally substituted 2-pyridyl, especially 3-methyl-2-pyridyl, are also preferred.
  • Compounds of formula (Ia) in which Ar1 represents an optionally substituted phenylene, especially optionally substituted m- or p-phenylene, more especially optionally substituted p-phenylene, are preferred. Compounds of formula (Ia) in which Ar1 represents 3-substituted p-phenylene, in which the substituent is ortho to the R3-NH-C(=O)-NH- group, are particularly preferred. Preferred optional substituents include halo, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, C1-4alkylsulphinyl and C1-4alkylsulphonyl, especially chloro, methyl, methoxy, methylthio, methylsulphinyl and methylsulphonyl.
  • Compounds of formula (Ia) in which Ar1 is an heteroaryldiyl, such as optionally substituted pyridinediyl, particularly a p-pyridinediyl, more particularly a pyridine-2,5-diyl, in which the R3-NH-C(=O)-NH- group is adjacent to the pyridyl nitrogen atom, and which is substituted in the 4- or 6-position, are also preferred. Preferred optional substituents include C1-4alkyl and C1-4alkoxy, especially methyl and methoxy.
  • Compounds of formula (Ia) in which L4 represents a straight or branched C1-6alkylene chain, more particularly a straight C1-4alkylene chain such as methylene or ethylene, especially methylene, are preferred.
  • Compounds of formula (Ia) in which A1 represents methylene are preferred.
  • Compounds of formula (Ia) in which A1 represents ethylene are also preferred.
  • Compounds of formula (Ia) in which Z1 represents CH2 are preferred.
  • Compounds of formula (Ia) in which R2 represents hydrogen are preferred.
  • Compounds of formula (Ia) in which L1 represents an optionally substituted alkylene linkage, particularly optionally substituted ethylene or optionally substituted propylene, especially ethylene optionally substituted with lower alkyl, aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9, -NY4Y5 or -[C(=O)-N(R10)-C(R5)(R11)]p-C(=O)-NY4Y5, or alkyl substituted by carboxy, -ZH, -ZR3, -C(=O)-NY4Y5 or -NY4Y5, are preferred. In one preferred embodiment L1 is a group
    Figure imgb0015
     [where R5 is hydrogen or lower alkyl (e.g. methyl) and R15 represents hydrogen or lower alkyl, or where R5 is hydrogen and R15 represents aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9, -NY4Y5 or -[C(=O)-N(R10)-C(R5)(R11)]p-C(=O)-NY4Y5, or alkyl substituted by carboxy, -ZH, -ZR3, -C(=O)-NY4Y5 or -NY4Y5], and is more preferably a group
    Figure imgb0016
     particularly
    Figure imgb0017
     [where R15 represents hydrogen, lower alkyl, aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9 or -NY4Y5 or alkyl substituted by carboxy, -OH, -OR3 or -C(=O)-NY4Y5]. In another preferred embodiment L1 is a group
    Figure imgb0018
     [where R5 is hydrogen or lower alkyl (e.g. methyl) and R15a represents lower alkyl, or where R5 is hydrogen and R15a represents aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9, -NY4Y5 or -[C(=O)-N(R10)-C(R5)(R11)]p-C(=O)-NY4Y5, or alkyl substituted by carboxy, -ZH, -ZR3, -C(=O)-NY4Y5 or -NY4Y5], and is more preferably a group
    Figure imgb0019
     particularly
    Figure imgb0020
     [where R15a represents -N(R8)-C(=O)-R9, or -N(R8)-SO2-R9).
  • A preferred group of compounds of the invention are compounds of formula (Ia) in which:- R2 is hydrogen; R3 is a 2-substituted phenyl [especially 2-methyl(or methoxy)phenyl]; A1 is methylene or ethylene; Ar1 is optionally substituted m- or p-phenylene (especially 3-chloro-p-phenylene, 3-methyl-p-phenylene, 3-methoxy-p-phenylene, 3-methylthio-p-phenylene, 3-methylsulphinyl-p-phenylene and 3-methylsulphonyl-p-phenylene) or optionally substituted p-pyridinediyl [especially 4(or 6)-methyl(or methoxy)-p-pyridine-2,5-diyl]; L1 is a
    Figure imgb0021
     group particularly a
    Figure imgb0022
     group, where R15 represents hydrogen, lower alkyl, aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9 or -NY4Y5, or alkyl substituted by carboxy, -OH, -OR3, -C(=O)-NY4Y5; L4 represents a straight or branched C1-6alkylene chain, especially methylene; Y represents carboxy; and Z1 represents CH2; and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  • Another preferred group of compounds of the invention are compounds of formula (Ia) in which:- R2 is hydrogen; R3 is a 2-substituted phenyl [especially 2-methyl(or methoxy)phenyl]; A1 is methylene or ethylene; Ar1 is optionally substituted m- or p-phenylene (especially 3-chloro-p-phenylene, 3-methyl-p-phenylene, 3-methoxy-p-phenylene, 3-methylthio-p-phenylene, 3-methylsulphinyl-p-phenylene and 3-methylsulphonyl-p-phenylene) or optionally substituted p-pyridinediyl [especially 4(or 6)-methyl(or methoxy)-p-pyridine-2,5-diyl]; L1 is a
    Figure imgb0023
     group, particularly
    Figure imgb0024
     [where R15a represents -N(R8)-C(=O)-R9, or -N(R8)-SO2-R9]; L4 represents a straight or branched C1-6alkylene chain, especially methylene; Y represents carboxy; and Z1 represents CH2; and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  • Another particular group of compounds of the invention are compounds of formula (Ib):-
    Figure imgb0025
     in which R2, R3, A1, L2, Y and Z1 are as hereinbefore defined, X is NR5 or O, Z4 represents a direct bond, NR5, O or S(O)n (where R5 and n are as hereinbefore defined), and R is hydrogen or an aryl group substituent, and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  • Compounds of formula (Ib) in which R3 represents aryl, especially 2-substituted phenyl, are preferred. Preferred optional substituents include lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy), halo (e.g. fluoro or chloro) and Y1Y2N- (e.g. dimethylamino). R3 especially represents ortho-tolyl.
  • Compounds of formula (Ib) in which Z4 represents NH are preferred.
  • Compounds of formula (Ib) in which R represents hydrogen, halo (e.g. chloro), lower alkyl (e.g. methyl or ethyl) or lower alkoxy (e.g. methoxy) are preferred.
  • Compounds of formula (Ib) in which L4 represents a straight or branched C1-6alkylene chain, especially a straight or branched C1-4alkylene chain, more especially methylene, are preferred.
  • Compounds of formula (Ib) in which A1 represents methylene are preferred.
  • Compounds of formula (Ib) in which A1 represents ethylene are also preferred.
  • Compounds of formula (Ib) in which Z1 represents CH2 are preferred.
  • Compounds of formula (Ib) in which R2 represents hydrogen are preferred.
  • Compounds of formula (Ib) in which L1 represents an optionally substituted alkylene linkage, particularly optionally substituted ethylene or optionally substituted propylene, especially ethylene optionally substituted with lower alkyl, aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9, -NY4Y5 or -[C(=O)-N(R10)-C(R5)(R11)]p-C(=O)-NY4Y5, or alkyl substituted by carboxy, -ZH, -ZR3, -C(=O)-NY4Y5 or -NY4Y5, are preferred. In one preferred embodiment L1 is a group
    Figure imgb0026
     [where R5 is hydrogen or lower alkyl (e.g. methyl) and R15 represents hydrogen or lower alkyl, or where R5 is hydrogen and R15 represents aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9, -NY4Y5 or -[C(=O)-N(R10)-C(R5)(R11)]p-C(=O)-NY4Y5, or alkyl substituted by carboxy, -ZH, -ZR3, -C(=O)-NY4Y5 or -NY4Y5], and is more preferably a group
    Figure imgb0027
     particularly
    Figure imgb0028
     [where R15 represents hydrogen, lower alkyl, aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9 or -NY4Y5 or alkyl substituted by carboxy, -OH, -OR3 or -C(=O)-NY4Y5]. In another preferred embodiment L1 is a group
    Figure imgb0029
     [where R5 is hydrogen or lower alkyl (e.g. methyl) and R15a represents lower alkyl, or where R5 is hydrogen and R15a represents aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9, -NY4Y5 or -[C(=O)-N(R10)-C(R5)(R11)]p-C(=O)-NY4Y5, or alkyl substituted by carboxy, -ZH, -ZR3, -C(=O)-NY4Y5 or -NY4Y5], and is more preferably a group
    Figure imgb0030
     particularly
    Figure imgb0031
     [where R15a represents -N(R8)-C(=O)-R9, or -N(R8)-SO2-R9].
  • The group
    Figure imgb0032
     may preferably be attached at the ring 6 position or the ring 5 or 6 position when X is NR5 and R5 is lower alkyl.
  • A preferred group of compounds of the invention are compounds of formula (Ib) in which:- R is hydrogen, chloro, methyl, ethyl or methoxy; R2 is hydrogen; R3 is aryl (especially ortho-tolyl); A1 is methylene or ethylene; L1 is a
    Figure imgb0033
     group particularly a
    Figure imgb0034
     group, where R15 represents hydrogen, lower alkyl, aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9 or -NY4Y5, or alkyl substituted by carboxy, -OH, -ZR3, -C(=O)-NY4Y5 or -NY4Y5; L4 is a straight or branched C1-4alkylene chain, especially methylene; X is O; Y is carboxy; Z1 is CH2; Z4 is NH; and the group
    Figure imgb0035
     is attached at the ring 6 position; and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs. Another preferred group of compounds of the invention are compounds of formula (Ib) in which:- R is hydrogen, chloro, methyl, ethyl or methoxy; R2 is hydrogen; R3 is aryl (especially ortho-tolyl); A1 is methylene or ethylene; L1 is a
    Figure imgb0036
     group, particularly
    Figure imgb0037
     [where R15a represents -N(R8)-C(=O)-R9, or -N(R8)-SO2-R9]; L4 is a straight or branched C1-4alkylene chain, especially methylene; X is O; Y is carboxy; Z1 is CH2; Z4 is NH; and the group
    Figure imgb0038
     is attached at the ring 6 position; and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  • Another preferred group of compounds of the invention are compounds of formula (Ib) in which:- R2 is hydrogen; R3 is aryl (especially ortho-tolyl); A1 is methylene or ethylene; L1 is a
    Figure imgb0039
     group particularly a
    Figure imgb0040
     group, where R15 represents hydrogen, lower alkyl, aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9 or -NY4Y5, or alkyl substituted by carboxy, -OH, -OR3, -C(=O)-NY4Y5 or -NY4Y5; L4 is a straight or branched C1-4alkylene chain, (especially methylene); X is NR5 (especially NH); Y is carboxy; Z1 is CH2; Z4 is NH; and the group
    Figure imgb0041
     is attached at the ring 5 or 6 position; and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  • Another preferred group of compounds of the invention are compounds of formula (Ib) in which:- R2 is hydrogen; R3 is aryl (especially ortho-tolyl); A1 is methylene or ethylene; L1 is a
    Figure imgb0042
     group, particularly
    Figure imgb0043
     [where R15a represents -N(R8)-C(=O)-R9, or -N(R8)-SO2-R9]; L4 is a straight or branched C1-4alkylene chain, (especially methylene); X is NR5 (especially NH); Y is carboxy; Z1 is CH2; Z4 is NH; and the group
    Figure imgb0044
     is attached at the ring 5 or 6 position; and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  • Another particular group of compounds of the invention are compounds of formula (Ic):-
    Figure imgb0045
     in which Ar1, L4, A1, R2, L1, Y and Z1 are as hereinbefore defined, and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  • Compounds of formula (Ic) in which Ar1 represents an optionally substituted phenylene, especially optionally substituted m- or p-phenylene, more especially optionally substituted p-phenylene, are preferred. Compounds of formula (Ic) in which Ar1 represents 3-substituted p-phenylene, in which the substituent is ortho to the
    Figure imgb0046
     group, are particularly preferred. Preferred optional substituents include halo, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, C1-4alkylsulphinyl and C1-4alkylsulphonyl, especially chloro, methyl, methoxy, methylthio, methylsulphinyl and methylsulphonyl
  • Compounds of formula (Ic) in which Ar1 is an heteroaryldiyl, such as optionally substituted pyridinediyl, particularly a p-pyridinediyl, more particularly a pyridine-2,5-diyl, in which the
    Figure imgb0047
     group is adjacent to the pyridyl nitrogen atom, and which is substituted in the 4- or 6-position,, are also preferred. Preferred optional substituents include C1-4alkyl and C1-4alkoxy, especially methyl and methoxy.
  • Compounds of formula (Ic) in which L4 represents a straight or branched C1-6alkylene chain, especially a straight or branched C1-4alkylene chain, more especially methylene, are preferred.
  • Compounds of formula (Ic) in which A1 represents methylene are preferred.
  • Compounds of formula (Ic) in which A1 represents ethylene are also preferred.
  • Compounds of formula (Ic) in which Z1 represents CH2 are preferred.
  • Compounds of formula (Ic) in which R2 represents hydrogen are preferred.
  • Compounds of formula (Ic) in which L1 represents an optionally substituted alkylene linkage, particularly optionally substituted ethylene or optionally substituted propylene, especially ethylene optionally substituted with lower alkyl, aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9, -NY4Y5 or -[C(=O)-N(R10)-C(R5)(R11)]p-C(=O)-NY4Y5, or alkyl substituted by carboxy, -ZH, -ZR3, -C(=O)-NY4Y5 or -NY4Y5, are preferred. In one preferred embodiment L1 is a group
    Figure imgb0048
     [where R5 is hydrogen or lower alkyl (e.g. methyl) and R15 represents hydrogen or lower alkyl, or where R5 is hydrogen and R15 represents aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9, -NY4Y5 or -[C(=O)-N(R10)-C(R5)(R11)]p-C(=O)-NY4Y5, or alkyl substituted by carboxy, -ZH, -ZR3, -C(=O)-NY4Y5 or -NY4Y5], and is more preferably a group
    Figure imgb0049
     particularly
    Figure imgb0050
     [where R15 represents hydrogen, lower alkyl, aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9 or -NY4Y5 or alkyl substituted by carboxy, -OH, -OR3 or -C(=O)-NY4Y5]. In another preferred embodiment L1 is a group
    Figure imgb0051
     [where R5 is hydrogen or lower alkyl (e.g. methyl) and R15a represents lower alkyl (e.g. methyl), or where R5 is hydrogen and R15a represents aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9, -NY4Y5 or -[C(=O)-N(R10)-C(R5)(R11)]p-C(=O)-NY4Y5, or alkyl substituted by carboxy, -ZH, -ZR3, -C(=O)-NY4Y5 or -NY4Y5], and is more preferably a group
    Figure imgb0052
     particularly
    Figure imgb0053
     [where R15a represents -N(R8)-C(=O)-R9, or -N(R8)-SO2-R9].
  • A preferred group of compounds of the invention are compounds of formula (Ic) in which:- R2 is hydrogen; A1 is methylene or ethylene; Ar1 is optionally substituted m- or p-phenylene (especially 3-chloro-p-phenylene, 3-methyl-p-phenylene, 3-methoxy-p-phenylene, 3-methylthio-p-phenylene, 3-methylsulphinyl-p-phenylene and 3-methylsulphonyl-p-phenylene) or optionally substituted p-pyridinediyl [especially 4(or 6)-methyl(or methoxy)-p-pyridine-2,5-diyl]; L1 is a
    Figure imgb0054
     group particularly a
    Figure imgb0055
     group, where R15 represents hydrogen, methyl, aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9 or -NY4Y5, or alkyl substituted by carboxy, -OH, -OR3 or -C(=O)-NY4Y5]; L4 is a straight or branched C1-4alkylene chain, (especially methylene); Y is carboxy; and Z1 is CH2; and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  • Another preferred group of compounds of the invention are compounds of formula (Ic) in which:- R2 is hydrogen; A1 is methylene or ethylene; Ar1 is optionally substituted m- or p-phenylene (especially 3-chloro-p-phenylene, 3-methyl-p-phenylene, 3-methoxy-p-phenylene, 3-methylthio-p-phenylene, 3-methylsulphinyl-p-phenylene and 3-methylsulphonyl-p-phenylene) or optionally substituted p-pyridinediyl [especially 4(or 6)-methyl(or methoxy)-p-pyridine-2,5-diyl]; L1 is a
    Figure imgb0056
     group, particularly
    Figure imgb0057
     [where R15a represents -N(R8)-C(=O)-R9, or -N(R8)-SO2-R9]; L4 is a straight or branched C1-4alkylene chain, (especially methylene); Y is carboxy; and Z1 is CH2; and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  • Another particular group of compounds of the invention are compounds of formula (Id):-
    Figure imgb0058
     in which R3, A1, R2, L1, Y and Z1 are as hereinbefore defined, and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  • Compounds of formula (Id) in which R3 represents aryl, especially optionally substituted phenyl, are preferred. Preferred optional substituents include aryloxy, cyano, halo (e.g. chloro or fluoro), lower alkoxy (e.g. methoxy), lower alkyl (e.g. methyl), nitro and perfluoroloweralkyl (e.g. trifluoromethyl). R3 especially represents 2-chlorophenyl, 5-chloro-2-cyanophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 4-fluoro-2-trifluoromethyl, 2-methyl-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2-nitrophenyl, 3-nitrophenyl and 2-phenoxyphenyl.
  • Compounds of formula (Id) in which R3 represents heteroaryl, especially isoquinolinyl, isoxazolyl, pyrazolopyrimidinyl, pyridyl, pyrimidinyl, quinolinyl, thiazolyl and triazolyl, each optionally substituted by one or more aryl group substituents, are preferred. Preferred optional substituents include alkyl-C(=O)-, aryl, cyano, halo, (e.g. chloro or fluoro), lower alkoxy (e.g. methoxy), lower alkyl (e.g. methyl), lower alkylsulphonyl, lower alkylthio, nitro and perfluoroloweralkyl (e.g. trifluoromethyl). R3 especially represents quinolin-4-yl, isoquinolin-2-yl, 2,4-pyridin-3-yl, 2,6-dimethyl-4-trifluoromethylpyridin-3-yl, 4-trifluoromethylpyridin3-yl, 2-phenyl-4-methyl-1,2,3-triazol-5-yl, 3,5-dimethylisoxazol-4-yl, 2,7-dimethylpyrazolofl,5-a]pyrimidin-6-yl, 2-isopropyl-4-methylthiazol-5-yl and 4-tritluoromethylpyrimidin-5-yl.
  • Compounds of formula (Id) in which R3 represents arylalkyl are also preferred. R3 especially represents optionally substituted benzyl, particularly 4-hydroxybenzyl, 3-chloro-4-hydroxybenzyl, 3-fluoro-4-hydroxybenzyl and 4-hydroxy-3-methoxybenzyl.
  • Compounds of formula (Id) in which A1 represents methylene are preferred.
  • Compounds of formula (Id) in which A1 represents ethylene are also preferred.
  • Compounds of formula (Id) in which Z1 represents CH2 are preferred.
  • Compounds of formula (Id) in which R2 represents hydrogen are preferred.
  • Compounds of formula (Id) in which L1 represents an optionally substituted alkylene linkage, particularly optionally substituted ethylene or optionally substituted propylene, especially ethylene optionally substituted with lower alkyl (e.g. methyl), aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9, -NY4Y5 or -[C(=O)-N(R10)-C(R5)(R11)]p-C(=O)-NY4Y5, or alkyl substituted by carboxy, -ZH, -ZR3, -C(=O)-NY4Y5 or -NY4Y5, are preferred. In one preferred embodiment L1 is a group
    Figure imgb0059
     [where R5 is hydrogen or lower alkyl (e.g. methyl) and R15 represents hydrogen or lower alkyl, or where R5 is hydrogen and R15 represents aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9, -NY4Y5 or -[C(=O)-N(R10)-C(R5)(R11)]p-C(=O)-NY4Y5, or alkyl substituted by carboxy, -ZH, -ZR3, -C(=O)-NY4Y5 or -NY4Y5], and is more preferably a group
    Figure imgb0060
     particularly
    Figure imgb0061
     [where R15 represents hydrogen, lower alkyl, aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9 or -NY4Y5 or alkyl substituted by carboxy, -OH, -OR3 or -C(=O)-NY4Y5]. In another preferred embodiment L1 is a group
    Figure imgb0062
     [where R5 is hydrogen or lower alkyl (e.g. methyl) and R15a represents lower alkyl, or where R5 is hydrogen and R15a represents aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9, -NY4Y5 or -[C(=O)-N(R10)-C(R5)(R11)]p-C(=O)-NY4Y5, or alkyl substituted by carboxy, -ZH, -ZR3, -C(=O)-NY4Y5 or -NY4Y5], and is more preferably a group
    Figure imgb0063
     particularly
    Figure imgb0064
     [where R15a represents -N(R8)-C(=O)-R9, or -N(R8)-SO2-R9].
  • A preferred group of compounds of the invention are compounds of formula (Id) in which:- R2 is hydrogen; R3 is optionally substituted phenyl (especially 2-chlorophenyl, 5-chloro-2-cyanophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 4-fluoro-2-trifluoromethyl, 2-methyl-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2-nitrophenyl, 3-nitrophenyl and 2-phenoxyphenyl), heteroaryl (especially quinolin-4-yl, isoquinolin-2-yl, 2,4-pyridin-3-yl, 2,6-dimethyl-4-trifluoromethylpyridin-3-yl, 4-trifluoromethylpyridin3-yl, 2-phenyl-4-methyl-1,2,3-triazol-5-yl, 3,5-dimethylisoxazol-4-yl, 2,7-dimethylpyrazolo-[1,5-a]pyrimidin-6-yl, 2-isopropyl-4-methylthiazol-5-yl and 4-trifluoromethylpyrimidin-5-yl) or optionally substituted benzyl (especially 4-hydroxybenzyl, 3-chloro-4-hydroxybenzyl, 3-fluoro-4-hydroxybenzyl and 4-hydroxy-3-methoxybenzyl); A1 is methylene or ethylene; L1 is a
    Figure imgb0065
     group particularly a
    Figure imgb0066
     group, where R15 represents hydrogen, methyl, aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9 or -NY4Y5, or alkyl substituted by carboxy, -OH, -OR3 or -C(=O)-NY4Y5]; Y is carboxy; and Z1 is CH2; and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  • Another preferred group of compounds of the invention are compounds of formula (Id) in which:- R2 is hydrogen; R3 is optionally substituted phenyl (especially 2-chlorophenyl, 5-chloro-2-cyanophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 4-fluoro-2-trifluoromethyl, 2-methyl-4-nitrophenyl, 2-inethyl-5-nitrophelay4 2-nitrophenyl, 3-nitrophenyl and 2-phenoxyphenyl), heteroaryl (especially quinolin-4-yl, isoquinolin-2-yl, 2,4-pyridin-3-yl, 2,6-dimethyl-4-trifluoromethylpyridin-3-yl, 4-trifluoromethylpyridin3-yl, optionally substituted benzyl (especially 4-hydroxybenzyl, 3-chloro-4-hydroaybenzyl, 3-fluoro-4-hydroxybenzyl and 4-hydroxy-3-methoxybenzyl); A1 is methylene or ethylene; L1 is a
    Figure imgb0067
     group, particularly
    Figure imgb0068
     [where R15a represents -N(R8)-C(=O)-R9, or -N(R8)-SO2-R9]; Y is carboxy; and Z1 is CH2; and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  • Compounds of formula (Ia), (Ib), (Ic) and (Id) in which R15 represents hydrogen are preferred.
  • Compounds of formula (Ia), (Ib), (Ic) and (Id) in which R15 represents lower alkyl (e.g. methyl, ethyl, propyl, butyl) are also preferred.
  • Compounds of formula (Ia), (Ib), (Ic) and (Id) in which R15 represents aryl (e.g. optionally substituted phenyl) are also preferred.
  • Compounds of formula (Ia), (Ib), (Ic) and (Id) in which R15 represents -N(R8)-C(=O)-R9, especially where R8 is hydrogen or lower alkyl (e.g. methyl) and R9 is lower alkyl (e.g. methyl), aryl (e.g. optionally substituted phenyl), heteroaryl (e.g. pyridyl, isoxazolyl, triazolyl, pyrimidinyl, thiazolyl, or pyrazolopyrimidinyl each optionally substituted by one or more aryl group substituents), alkyl substituted by alkoxy (e.g. -CH2-O-CH2-CH2-OCH3), alkyl substituted by carboxy (e.g. -CH2-CH2-CO2H and -CH2-CH2-CH2-CO2H) or alkyl substituted by -NY4Y5 (e.g. aminomethyl and morpholin-1-ylmethyl), are preferred.
  • Compounds of formula (Ia), (Ib), (Ic) and (Id) in which R15 represents -N(R8)-C(=O)-OR9, especially where R8 is hydrogen or lower alkyl (e.g. methyl) and R9 is lower alkyl (e.g. ethyl) or alkyl substituted by aryl (e.g. benzyl), are also preferred.
  • Compounds of formula(Ia), (Ib), (Ic) and (Id) in which R15 represents -N(R8)-SO2-R9, especially where R8 is hydrogen or lower alkyl (e.g. methyl) and R9 is lower alkyl (e.g. methyl), aryl [e.g. optionally substituted phenyl or optionally substituted naphthyl (especially dimethylaminonaphth-1-yl)]), heteroaryl (e.g. optionally substituted pyridyl or optionally substituted imidazolyl), are also preferred.
  • Compounds of formula (Ia), (Ib), (Ic) and (Id) in which R15 represents -NY4Y5, especially where Y4 and Y5 represent hydrogen are also preferred.
  • Compounds of formula (Ia), (Ib), (Ic) and (Id) in which R15 represents -NY4Y5, especially where Y4 is hydrogen and Y5 is or lower alkyl (e.g. propyl), or alkyl substituted by aryl (e.g. -CH2-Ph or -CH2-CH2-Ph), are also preferred.
  • Compounds of formula (Ia), (Ib), (Ic) and (Id) in which R15 represents -NY4Y5, especially where Y4 and Y5 represent alkyl substituted by aryl (e.g. -CH2-Ph or -CH(CH3)-Ph), are also preferred.
  • Compounds of formula (Ia), (Ib), (Ic) and (Id) in which R15 represents alkyl substituted by carboxy, especially lower alkyl substituted by carboxy (e.g. carboxymethyl), are also preferred.
  • Compounds of formula (Ia), (Ib), (Ic) and (Id) in which R15 represents alkyl substituted by -OH, especially lower alkyl substituted by -OH (e.g. hydroxymethyl), are also preferred.
  • Compounds of formula (Ia), (Ib), (Ic) and (Id) in which R15 represents alkyl substituted by -OR3, especially lower alkyl substituted by -OR3 (e.g. methoxymethyl), are also preferred.
  • Compounds of formula(Ia), (Ib), (Ic) and (Id) in which R15 represents alkyl substituted by -C(=O)-NY4Y5, especially lower alkyl substituted by -C(=O)-NY4Y5 (e.g.
    Figure imgb0069
     are also preferred.
  • Particularly preferred compounds of formula (Ia), (Ib), (Ic) and (Id) are those in which R15 is -H, -NH2, -NHCH2CH2CH3,
    Figure imgb0070
    Figure imgb0071
    Figure imgb0072
    Figure imgb0073
    Figure imgb0074
    Figure imgb0075
    Figure imgb0076
    Figure imgb0077
    Figure imgb0078
    Figure imgb0079
     (in which R is hydrogen or an aryl group substituent), -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2-OH, -CH2-CO2H or -CH2-OMe.
  • Compounds of formula (Ia), (Ib), (Ic) and (Id) in which R15a represents -N(R8)-C(=O)-R9, especially where R8 is hydrogen or lower alkyl (e.g. methyl) and R9 is lower alkyl (e.g. methyl), aryl (e.g. optionally substituted phenyl), heteroaryl (e.g. pyridyl, isoxazolyl, triazolyl, pyrimidinyl, thiazolyl, or pyrazolopyrimidinyl each optionally substituted by one or more aryl group substituents), alkyl substituted by alkoxy (e.g. -CH2-O-CH2-CH2-OCH3), alkyl substituted by carboxy (e.g. -CH2-CH2-CO2H and -CH2-CH2-CH2-CO2H) or alkyl substituted by -NY4Y5 (e.g. aminomethyl and morpholin-1-ylmethyl), are preferred.
  • Compounds of formula (Ia), (Ib), (Ic) and (Id) in which R15a represents -N(R8)-C(=O)-R9 where R9 is substituted phenyl selected from 2-chlorophenyl, 5-chloro-2-cyanophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 4-fluoro-2-trifluoromethyl, 2-methyl-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2-nitrophenyl, 3-nitrophenyl or 2-phenoxyphenyl are particularly preferred.
  • Compounds of formula (Ia), (Ib), (Ic) and (Id) in which R15a represents -N(R8)-C(=O)-R9 where R9 is an optionally substituted heteroaryl selected from quinolin-4-yl, isoquinolin-2-yl, 2,4-pyridin-3-yl, 2,6-dimethyl-4-trifluoromethylpyridin-3-yl, 4-trifluoromethylpyridin3-yl, 2-phenyl-4-methyl-1,2,3-triazol-5-yl, 3,5-dimethylisoxazol-4-yl, 2,7-dimethylpyrazolo-[1,5-a]pyrimidin-6-yl, 2-isopropyl-4-methylthiazol-5-yl and 4-trifluoromethylpyrimidin-5-yl are also particularly preferred.
  • Particular compounds of the invention are selected from the compounds formed by joining the acyl carbon atom (C*) of one of the fragments (A1 to A34) shown in Table 1 to the nitrogen atom (N*) of one of the aza-bicyclic fragments (B1 to B6) shown in Table 2, and joining the carbon atom (C*) of the phenyl ring in one of the aza-bicyclic fragments (B1 to B6) shown in Table 2 to the carbon atom (C*) of one of the acidic fragments (C1 to C59) depicted in Table 3. TABLE 1
    A1
    Figure imgb0080
         		A2
    Figure imgb0081
    A3
    Figure imgb0082
         		A4
    Figure imgb0083
    A5
    Figure imgb0084
         		A6
    Figure imgb0085
    A7
    Figure imgb0086
         		A8
    Figure imgb0087
    A9
    Figure imgb0088
         		A10
    Figure imgb0089
    A11
    Figure imgb0090
         		A12
    Figure imgb0091
    A13
    Figure imgb0092
         		A14
    Figure imgb0093
    A15
    Figure imgb0094
         		A16
    Figure imgb0095
    A17
    Figure imgb0096
         		A18
    Figure imgb0097
    A19
    Figure imgb0098
         		A20
    Figure imgb0099
    A21
    Figure imgb0100
         		A22
    Figure imgb0101
    A23
    Figure imgb0102
         		A24
    Figure imgb0103
    A25
    Figure imgb0104
         		A26
    Figure imgb0105
    A27
    Figure imgb0106
         		A28
    Figure imgb0107
    A29
    Figure imgb0108
         		A30
    Figure imgb0109
    A31
    Figure imgb0110
         		A32
    Figure imgb0111
    A33
    Figure imgb0112
         		A34
    Figure imgb0113
    A35
    Figure imgb0114
    TABLE 2
    B1
    Figure imgb0115
         		B2
    Figure imgb0116
    B3
    Figure imgb0117
         		B4
    Figure imgb0118
    B5
    Figure imgb0119
         		B6
    Figure imgb0120
    TABLE 3
    C1 *CH2-CH2-CO2H C2
    Figure imgb0121
    C3
    Figure imgb0122
         		C4
    Figure imgb0123
    C5
    Figure imgb0124
         		C6
    Figure imgb0125
    C7
    Figure imgb0126
         		C8
    Figure imgb0127
    C9
    Figure imgb0128
         		C10
    Figure imgb0129
    C11
    Figure imgb0130
         		C12
    Figure imgb0131
    C13
    Figure imgb0132
         		C14
    Figure imgb0133
    C15
    Figure imgb0134
         		C16
    Figure imgb0135
    C17
    Figure imgb0136
         		C18
    Figure imgb0137
    C19
    Figure imgb0138
         		C20
    Figure imgb0139
    C21
    Figure imgb0140
         		C22
    Figure imgb0141
    C23
    Figure imgb0142
         		C24
    Figure imgb0143
    C25
    Figure imgb0144
         		C26
    Figure imgb0145
    C27
    Figure imgb0146
         		C28
    Figure imgb0147
    C29
    Figure imgb0148
         		C30
    Figure imgb0149
    C31
    Figure imgb0150
         		C32
    Figure imgb0151
    C33
    Figure imgb0152
         		C34
    Figure imgb0153
    C35
    Figure imgb0154
         		C36
    Figure imgb0155
    C37 C39
    Figure imgb0156
    Figure imgb0157
         		C38 C40
    Figure imgb0158
    Figure imgb0159
    C41
    Figure imgb0160
         		C42
    Figure imgb0161
    C43
    Figure imgb0162
         		C44
    Figure imgb0163
    C45
    Figure imgb0164
         		C46
    Figure imgb0165
    C47
    Figure imgb0166
         		C48
    Figure imgb0167
    C49
    Figure imgb0168
         		C50
    Figure imgb0169
    C51
    Figure imgb0170
         		C52
    Figure imgb0171
    C53
    Figure imgb0172
         		C54
    Figure imgb0173
    C55
    Figure imgb0174
         		C56
    Figure imgb0175
    C57
    Figure imgb0176
         		C58
    Figure imgb0177
    C59
    Figure imgb0178
  • Particular compounds of the invention are:-
    Figure imgb0179
    Figure imgb0180
    Figure imgb0181
    Figure imgb0182
    Figure imgb0183
    Figure imgb0184
    Figure imgb0185
    Figure imgb0186
    Figure imgb0187
    Figure imgb0188
    Figure imgb0189
    Figure imgb0190
    Figure imgb0191
    Figure imgb0192
    Figure imgb0193
    Figure imgb0194
    Figure imgb0195
    Figure imgb0196
    Figure imgb0197
    Figure imgb0198
    Figure imgb0199
    Figure imgb0200
    Figure imgb0201
    Figure imgb0202
    Figure imgb0203
    Figure imgb0204
    Figure imgb0205
    Figure imgb0206
    Figure imgb0207
    Figure imgb0208
    Figure imgb0209
    Figure imgb0210
    Figure imgb0211
    Figure imgb0212
    Figure imgb0213
    Figure imgb0214
    Figure imgb0215
    Figure imgb0216
    Figure imgb0217
    Figure imgb0218
    Figure imgb0219
    Figure imgb0220
    Figure imgb0221
    Figure imgb0222
    Figure imgb0223
    Figure imgb0224
    Figure imgb0225
    Figure imgb0226
    Figure imgb0227
    Figure imgb0228
    Figure imgb0229
    Figure imgb0230
    Figure imgb0231
    Figure imgb0232
    Figure imgb0233
    Figure imgb0234
    Figure imgb0235
    Figure imgb0236
    Figure imgb0237
    Figure imgb0238
    Figure imgb0239
    Figure imgb0240
    Figure imgb0241
    Figure imgb0242
    Figure imgb0243
    Figure imgb0244
    Figure imgb0245
    Figure imgb0246
    Figure imgb0247
    Figure imgb0248
    Figure imgb0249
    Figure imgb0250
     and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  • Thus, for example, in the above list the compound denoted as A1-B1-C1 is the product of the combination of group A1 in Table 1 and B1 in Table 2 and C1 in Table 3, namely
    Figure imgb0251
  • Preferred compounds of the invention are:-
    • 3-(1-{[3-methoxy-4-(3-[2-methylphenyl]-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinoliu-6-yl)-propionic acid;
    • 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indel-5-yl)-butyric acid;
    • 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-butyric acid;
    • 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-pentanedioic acid;
    • 3-(1-{[3-methogy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-pentanedioic acid;
    • 4-[2-carboxy-1-(1-{[3-methozy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-ethylcarbamoyl]-butyric acid;
    • N-[2-carboxy-1-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-suceinamic acid;
    • 3-(1-{[3-methoary-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-3-[(5-methyl-isoxazole-3-carbonyl)-amino]-propionic acid;
    • 2-(2-chloro-6-methyl-benzoylamino)-[1-(2,6-dichloro-benzoyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-propionic acid;
    • 2-(2,6-dichloro-benzoylamino)-3-[1-(2,6-dichloro-benzoyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-propionic acid;
    • 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-3-phenylpropionic acid;
    • 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-pentanoic acid;
    and the corresponding N-oxide, and its ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  • The compounds of the invention exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. The present invention thus provides, according to a further aspect, compounds of the invention and compositions containing compounds of the invention for use in therapy.
  • Compounds within the scope of the present invention block the interaction of the ligand VCAM-1 to its integrin receptor VLA-4 (α4β1) according to tests described in the literature and described in vitro and in vivo procedures hereinafter, and which tests results are believed to correlate to pharmacological activity in humans and other mammals. Thus, in a further embodiment, the present invention provides compounds of the invention and compositions containing compounds of the invention for use in the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of α4β1 mediated cell adhesion. For example, compounds of the present invention are useful in the treatment of inflammatory diseases, for example joint inflammation, including arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and osteoarthritis. Additionally, the compounds may be useful in the treatment of acute synovitis, autoimmune diabetes, autoimmune encephalomyelitis, collitis, atherosclerosis, peripheral vascular disease, cardiovascular disease, multiple sclerosis, asthma, psoriasis restenosis, myocarditis, inflammatory bowel disease and melanoma cell division in metastasis.
  • A special embodiment of the therapeutic methods of the present invention is the treating of asthma.
  • Another special embodiment of the therapeutic methods of the present invention is the treating of joint inflammation.
  • Another special embodiment of the therapeutic methods of the present invention is the treating of inflammatory bowel disease.
  • According to a further feature of the invention there is provided a method for the treatment of a human or animal patient suffering from, or subject to, conditions which can be ameliorated by
  • According to a further feature of the invention there is provided a method for the treatment of a human or animal patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of the interaction of the ligand VCAM-1 to its integrin receptor VLA-4 (α4β1), for example conditions as hereinbefore described, which comprises the administration to the patient of an effective amount of compound of the invention or a composition containing a compound of the invention. "Effective amount" is meant to describe an amount of compound of the present invention effective in inhibiting the interaction of the ligand VCAM-1 to its integrin receptor VLA-4(α4β1), and thus producing the desired therapeutic effect.
  • References herein to treatment should be understood to include prophylactic therapy as well as treatment of established conditions.
  • The present invention also includes within its scope pharmaceutical compositions comprising at least one of the compounds of the invention in association with a pharmaceutically acceptable carrier or excipient.
  • Compounds of the invention may be administered by any suitable means. In practice compounds of the present invention may generally be administered parenterally, topically, rectally, orally or by inhalation, especially by the oral route.
  • Compositions according to the invention may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients. The adjuvants comprise, inter alia, diluents, sterile aqueous media and the various non-toxic organic solvents. The compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and can contain one or more agents chosen from the group comprising sweeteners, flavourings, colourings, or stabilisers in order to obtain pharmaceutically acceptable preparations. The choice of vehicle and the content of active substance in the vehicle are generally determined in accordance with the solubility and chemical properties of the active compound, the particular mode of administration and the provisions to be observed in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used for preparing tablets. To prepare a capsule, it is advantageous to use lactose and high molecular weight polyethylene glycols. When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension.
  • Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.
  • For parenteral administration, emulsions, suspensions or solutions of the products according to the invention in vegetable oil, for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, are used. The solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection. The aqueous solutions, also comprising solutions of the salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilised by heating, irradiation or microfiltration.
  • For topical administration, gels (water or alcohol based), creams or ointments containing compounds of the invention may be used. Compounds of the invention may also be incorporrated in a gel or matrix base for application in a patch, which would allow a controlled release of compound through the transdermal barrier.
  • For administration by inhalation compounds of the invention may be dissolved or suspended in a suitable carrier for use in a nebuliser or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler.
  • Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of the invention.
  • The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time. The dose employed will be determined by the physician, and depends upon the desired therapeutic effect the route of administration and the duration of the treatment, and the condition of the patient, In the adult, the doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation, from about 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from about 0.001 to about 10, preferably 0.01 to 1, mg/kg body weight per day by intravenous administration. In each particular case, the doses will be determined in accordance with the factors distinctive to the subject to be treated, such as age, weight, general state of health and other characteristics which can influence the efficacy of the medicinal product.
  • The compounds according to the invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. Of course, for some patients, it will be necessary to prescribe not more than one or two doses per day.
  • Compounds of the invention may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, for example those described by R.C.Larock in Comprehensive Organic Transformations, VCH publishers, 1989.
  • In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T.W. Greene and P.G.M.Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.
  • Compounds of formula (I), wherein R1, R2, A1, L1 and Z1 are as hereinbefore defined, and where Y is carboxy, may be prepared by hydrolysis of esters of formula (I), wherein R1, R2, A1, L1 and Z1 are as hereinbefore defined and Y is a -CO2R16 group (in which R16 is alkyl, alkenyl or arylalkyl). The hydrolysis may conveniently be carried out by alkaline hydrolysis using a base, such as an alkali metal hydroxide, e.g. sodium hydroxide or lithium hydroxide, or an alkali metal carbonate, e.g. potassium carbonate, in the presence of an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol, at a temperature from about ambient temperature to about reflux temperature. The hydrolysis of the esters may also be carried out by acid hydrolysis using an inorganic acid, such as hydrochloric acid, in the presence of an aqueous/inert organic solvent mixture, using organic solvents such as dioxan or tetrahydrofuran, at a temperature from about 50°C to about 80°C.
  • As another example compounds of formula (I), wherein R1, R2, A1, L1 and Z1 are as hereinbefore defined, and where Y is carboxy, may be prepared by acid catalysed removal of the tert-butyl group of tert-butyl esters of formula (I), wherein R1, R2, A1, L1 and Z1 are as hereinbefore defined and Y is a -CO2R16 group (in which R16 is tert-butyl), using standard reaction conditions, for example reaction with trifluoroacetic acid at a temperature at about room temperature.
  • As another example compounds of formula (I), wherein R1, R2, A1, L1 and Z1 are as hereinbefore defined, and where Y is carboxy, may be prepared by hydrogenation of compounds of formula (I) wherein R1, R2, A1, L1 and Z1 are as hereinbefore defined and Y is a -CO2R16 group (in which R16 is arylmethyl, e.g. benzyl). The reaction may be carried out in the presence of ammonium formate and a suitable metal catalyst, e.g. palladium, supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol and at a temperature at about reflux temperature. The reaction may alternatively be carried out in the presence of a suitable metal catalyst, e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol. This reaction is most suitable for compounds of formula (I) where L1 does not contain carbon-carbon multiple bonds.
  • In a process A compounds of formula (I), containing an amide bond may be prepared by coupling of an acid (or an acid halide) with an amine to give an amide bond using standard peptide coupling procedures as described hereinafter.
  • As an example of process A, compounds of formula (I) wherein R2, A1, L1, Y and Z1 are as hereinbefore defined and R1 is a group selected from R3-Z3-, R3-L2-R4-Z3-, R3-L3-Ar1-L4-Z3- or R3-L3-Ar1-L2-R4-Z3- [in which R3, R4, L2, L3, L4 and Ar1 are as hereinbefore defined and
    • Z3 is C(=O)] may be prepared by:-
      • (i) treating bromo-Wang resin (4-bromomethylphenoxylated styrene/divinylbenzene copolymer) with an acid of formula (II) wherein A1, Z1, R2, and L1 are as hereinbefore defined and R17 is a suitable imino-protecting group, such as 9H-fluoren-9-ylmethoxylcarbonyl, in the presence of a tertiary amine, such as diisopropylethylamine, and cesium iodide, in an inert solvent, such as dimethylformamide, at a temperature at about room temperature, to give Resin A:
        Figure imgb0252
         where
        Figure imgb0253
         represents the polymeric core comprising polystyrene crosslinked with 1% to 2% divinylbenzene;
      • (ii) treatment of Resin A with piperidine in an inert solvent, such as dimethylformamide, and at a temperature at about room temperature to give Resin B:-
        Figure imgb0254
         wherein A1, Z1, R2, L1 and
        Figure imgb0255
         are as hereinbefore defined;
      • (iii) Reaction of Resin B with compounds of formula (III) wherein R18 is R3-, R3-L2-R4-, R3-L3-Ar1-L4- or R3-L3-Ar1-L2-R4- (in which R3, R4, L2, L3, Ar1 and L4 are as hereinbefore defined) and X1 is a hydroxy group or a halogen, preferably chlorine, atom to give Resin C wherein R2, R18, A1, Z1, L1 and
        Figure imgb0256
         are as hereinbefore defined [When X1 is a hydroxy group the reaction may be carried out using standard peptide coupling procedures for example coupling in the presence of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and triethylamine (or diisopropylethylamine) in tetrahydrofuran (or dimethylformamide), at room temperature. When X1 is a halogen atom the acylation reaction may be carried out with the aid of a base, such pyridine, preferably in a solvent such as tetrahydrofuran and at a temperature at about room temperature];
        Figure imgb0257
      • (iv) treatment of Resin C with trifluoroacetic acid in an inert solvent, such as dichloromethane, and at a temperature at about room temperature.
  • As another example of process A, compounds of formula (I) wherein R1, R2, A1, Y and Z1 are as hereinbefore defined and L1 contains a -N(R8)-C(=O)-R9 group (in which R8 and R9 are as hereinbefore defined) may be prepared by reaction of the corresponding compounds of formula (I) wherein R1, R2, A1, Y and Z1 are as hereinbefore defined and L1 contains a -NH(R8) group (in which R8 is as hereinbefore defined) with acids (or acid chlorides) of formula R9-C(=O)-X1 wherein R9 and X1 are as hereinbefore defined, using standard coupling conditions, for example those described hereinbefore.
  • Esters of formula (I), wherein R1, R2, A1 and Z1 are as hereinbefore defined, Y is a -CO2R16 group (in which R16 is as hereinbefore defined) and L1 contains a -N(R8)-C(=O)-R9 group (in which R8 and R9 are as hereinbefore defined) may be similarly prepared from the corresponding esters of formula (I) where L1 contains a -NHR8 group (in which R8 is as hereinbefore defined) by reaction with a compound of formula R9-C(=O)-X1 wherein R9 and X1 are as hereinbefore defined.
  • Esters of formula (I), wherein R2, A1, L1 and Z1 are as hereinbefore defined, R1 is a group selected from R3-Z3-, R3-L2-R4-Z3-, R3-L3-Ar1-L4-Z3- or R3-L3-Ar1-L2-R4-Z3- [in which R3, R4, L2, L3, L4 and Ar1 are as hereinbefore defined and Z3 is C(=O)] and Y is a -CO2R16 group (in which R16 is as hereinbefore defined), may be prepared by reacting a compound of formula (III) wherein R18 is R3-, R3-L2-R4-, R3-L3-Ar1-L4- or R3-L3-Ar1-L2-R4- (in which R3, R4, L2, L3, Ar1 and L4 are as hereinbefore defined) and X1 is a hydroxy group, a halogen, preferably chlorine, atom with an amine of formula (IV):-
    Figure imgb0258
     wherein R2, A1, L1, Z1 and R16 are as hereinbefore defined, using standard coupling conditions, for example those described hereinbefore.
  • Esters of formula (I), wherein R1, R2, A1 and Z1 are as hereinbefore defined, Y is a -CO2R16 group (in which R16 is as hereinbefore defined) and L1 contains a -N(R8)-SO2-R9 group (in which R8 and R9 are as hereinbefore defined), may be similarly prepared from the corresponding esters of formula (I) where L1 contains a -NHR8 group (in which R8 is as hereinbefore defined) by reaction with sulphonyl chlorides of formula R9-SO2Cl wherein R9 is as hereinbefore defined.
  • Esters of formula (I), wherein R1, R2, A1 and Z1 are as hereinbefore defined, Y is a -CO2R16 group (in which R16 is as hereinbefore defined) and L1 contains a -NHR8 group (in which R8 is alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl), may be similarly prepared by alkylation of the corresponding derivatives of formula (I) where L1 contains a -NH2 group, with the appropriate alkyl (or arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl) halide.
  • Esters of formula (I), wherein R1, R2, A1 and Z1 are as hereinbefore defined, Y is a -CO2R16 group (in which R16 is as hereinbefore defined) and L1 contains a -N(R8)-C(=O)-OR9 group (in which R8 and R9 are as hereinbefore defined), may be similarly prepared from the corresponding derivatives of formula (I) where L1 contains a -NHR8 group (in which R8 is as hereinbefore defined) by reaction with compounds of formula R9O-C(=O)-X3 wherein R9 and X3 are as hereinbefore defined.
  • Esters of formula (I), wherein R1, R2, A1 and Z1 are as hereinbefore defined, Y is a -CO2R16 group (in which R16 is as hereinbefore defined) and L1 is
    Figure imgb0259
     (or
    Figure imgb0260
     may be prepared by hydrogenation of the corresponding derivatives of formula (I), where L1 is
    Figure imgb0261
     The reaction may be carried out in the presence of formic acid and a suitable metal catalyst, e.g. palladium, supported on an inert carrier such as carbon, at a temperature at about 60°C. The reaction may conveniently be carried out in the presence of a suitable metal catalyst, e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol.
  • Esters of formula (I), wherein R1, R2, A1 and Z1 are as hereinbefore defined, Y is a -CO2R16 group (in which R16 is as hereinbefore defined) and L1 is a
    Figure imgb0262
     (or
    Figure imgb0263
     linkage, may also be obtained from the racemic mixture following standard recrystallisation of a suitable salt (for example recrystallisation of the tartrate salt), or by the application of standard enzymatic resolution procedures (for example those described by Soloshonok, V. A., et. al., Tetrahedron: Asymmetry 6 (1995) 7,1601-1610).
  • Esters of formula (I), wherein R1, R2, A1 and Z1 are as hereinbefore defined, Y is a -CO2R16 group (in which R16 is as hereinbefore defined) and L1 is a
    Figure imgb0264
     or
    Figure imgb0265
     linkage, may be prepared by reacting an ester of formula (I), wherein R1, R2, A1 and Z1 are as hereinbefore defined, Y is a -CO2R16 group (in which R16 is as hereinbefore defined) and L1 is a -CH=CH- linkage, with an alkali metal hydride, such as sodium hydride, in an inert solvent, e.g. tetrahydrofuran, and at a temperature at about room temperature, and subsequent reaction with the anion derived from treating dibenzylamine, or (S)-N-benzyl-α-methylbenzylamine, with butyllithium, at a temperature at about -78°C.
  • Esters of formula (I), wherein R1, R2, A1 and Z1 are as hereinbefore defined, Y is a -CO2R16 group (in which R16 is as hereinbefore defined) and L1 contains an alkenylene, alkynylene or cycloalkenylene in which the aliphatic carbon-carbon multiple bond is attached directly to the phenyl moiety in formula (I), may be prepared by coupling of compounds of formula (IX):-
    Figure imgb0266
     wherein R1, R2, A1 and Z1 are as hereinbefore defined and X4 is a halogen, preferably bromine or iodine, atom with a compound of formula (X):-

            R19-CO2R16     (X)

    wherein R16 is as hereinbefore defined and R19 is alkenyl, alkynyl or cycloalkenyl When X4 is a bromine or iodine atom the reaction may be conveniently carried out in the presence of palladium acetate, a triarylphosphine, such as tri-o-tolylphosphine, and a tertiary amine, such as tributylamine, at a temperature up to about 110°C. This reaction is particularly suitable for the preparation of esters of formula (I) in which L1 is vinylene. When X4 is a chlorine atom the reaction may be conveniently carried out in the presence of sodium iodide, nickel bromide, palladium(0) bis(dibenzylideneacetone), a triarylphosphine, such as tri-o-tolylphosphine, and a tertiary amine, such as tributylamine, at a temperature up to about 110°C.
  • Compounds of the invention may be prepared by interconversion of other compounds of the invention.
  • As another example of the interconversion process, compounds of formula (I) containing sulphoxide linkages may be prepared by the oxidation of corresponding compounds containing -S- linkages. For example, the oxidation may conveniently be carried out by means of reaction with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature, or alternatively by means of potassium hydrogen peroxomonosulphate in a medium such as aqueous methanol, buffered to about pH5, at temperatures between about 0°C and room temperature. This latter method is preferred for compounds containing an acid-labile group.
  • As another example of the interconversion process, compounds of formula (I) containing sulphone linkages may be prepared by the oxidation of corresponding compounds containing -S- or sulphoxide linkages. For example, the oxidation may conveniently be carried out by means of reaction with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature.
  • As another example of the interconversion process, compounds of formula (I), wherein R1, R2, A1, Z1 and Y are as hereinbefore defined, and L1 is optionally substituted alkylene, may be prepared by hydrogenation of the corresponding compounds of formula (I) in which L1 is the corresponding optionally substituted alkenylene. The hydrogenation may be carried out using hydrogen (optionally under pressure) in the presence of a suitable metal catalyst, e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol, and at a temperature at about room temperature.
  • As another example of the interconversion process, compounds of formula (I), wherein R1, R2, A1, L1 and Z1 are as hereinbefore defined, L1 is an alkylene linkage substituted by -CONY4Y5 and Y is carboxy, may be prepared by reacting compounds of formula (I), wherein R1, R2, A1, L1 and Z1 are as hereinbefore defined, L1 is an alkylene linkage substituted by -CO2H and Y is carboxy, with an anhydride, such as trifluoroacetic anhydride, in an inert solvent e.g. tetrahydrofuran, followed by treatment with an amine HNY4Y5.
  • As another example of the interconversion process, compounds of formula (I), wherein R1, R2, A1, L1 and Y are as hereinbefore defined, and Z1 is C(=O) may be prepared by oxidation of compounds of formula (I), wherein R1, R2, A1, L1 and Y are as hereinbefore defined, and Z1 is CH2. For example the oxidation may conveniently be carried out by reaction with potassium permanganate.
  • As another example of the interconversion process, compounds of formula (I), wherein R1, R2, A1, L1 and Y are as hereinbefore defined, and Z1 is CH(OH) may be prepared by reduction of compounds of formula (I), wherein R1, R2, A1, L1 and Y are as hereinbefore defined, and Z1 is C(=O). For example the reduction may conveniently be carried out by reaction with sodium borohydride in aqueous ethanol at a temperature at about room temperature.
  • As another example of the interconversion process, compounds of the invention containing a heterocyclic group wherein the hetero atom is a nitrogen atom may be oxidised to their corresponding N-oxides. The oxidation may conveniently be carried out by means of reaction with a mixture of hydrogen peroxide and an organic acid, e.g. acetic acid, preferably at or above room temperature, for example at a temperature of about 60-90°C. Alternatively, the oxidation may be carried out by reaction with a peracid, for example peracetic acid or m-chloroperoxybenzoic acid, in an inert solvent such as chloroform or dichloromethane, at a temperature from about room temperature to reflux, preferably at elevated temperature. The oxidation may alternatively be carried out by reaction with hydrogen peroxide in the presence of sodium tungstate at temperatures between room temperature and about 60°C.
  • It will be appreciated that compounds of the present invention may contain asymmetric centres. These asymmetric centres may independently be in either the R or S configuration. It will be apparent to those skilled in the art that certain compounds of the invention may also exhibit geometrical isomerism. It is to be understood that the present invention includes individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures, of compounds of formula (I) hereinabove. Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallisation techniques, or they are separately prepared from the appropriate isomers of their intermediates.
  • According to a further feature of the invention, acid addition salts of the compounds of this invention may be prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods. For example, the acid addition salts of the compounds of this invention may be prepared either by dissolving the free base in water or aqueous alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
  • The acid addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
  • Compounds of this invention can be regenerated from their base addition salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.
  • Compounds of the present invention may be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallisation from an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol.
  • According to a further feature of the invention, base addition salts of the compounds of this invention may be prepared by reaction of the free acid with the appropriate base, by the application or adaptation of known methods. For example, the base addition salts of the compounds of this invention may be prepared either by dissolving the free acid in water or aqueous alcohol solution or other suitable solvents containing the appropriate base and isolating the salt by evaporating the solution, or by reacting the free acid and base in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
  • The starting materials and intermediates may be prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their obvious chemical equivalents.
  • Compounds of formula (III) wherein R18 is R3-L3-Ar1-L4- group (in which R3, R4, L2, L3, L4 and Ar1 are as hereinbefore defined) may be prepared by the application or adaptation of methods described in the specification of International Patent Application Publication No. WO 96/22966.
  • Acids of formula (III) wherein R18 is R3-L3-Ar1-L4- (in which R3 and L4 are as defined above, L3 is NH, Ar1 is
    Figure imgb0267
     (in which R is as hereinbefore defined) and X1 is a hydroxy group may be prepared by reaction of compounds of formula (1):-
    Figure imgb0268
     wherein R and L4 are as hereinbefore defined, R16 is lower alkyl and X is O, with isocyanates of formula R3-N=C=O (in which R3 is as hereinbefore defined) in ethanol and at room temperature, followed by reaction with a carbodiimide, such as dicyclohexylcarbodiimide or diisopropylcarbodiimide in ethanol and at a temperature from about room temperature to about reflux temperature, and subsequent hydrolysis using standard conditions, for example those described hereinbefore.
  • Acids of formula (III) wherein R18 is R3-L3-Ar1-L4- (in which R3 and L4 are as hereinbefore defined, Ar1 is
    Figure imgb0269
     (in which R is as hereinbefore defined), L3 is NH and X1 is hydroxy may be similarly prepared from compounds of formula (1) wherein R, L4 and R16 are as hereinbefore defined and X is NH.
  • Acid chlorides of formula (III) wherein R18 is as hereinbefore defined and X1 is a chlorine atom may be prepared from the corresponding acids of formula (II) wherein R18 is as hereinbefore defined and X1 is hydroxy, by the application of standard procedures for the conversion of acids to acid chlorides for example by reaction with oxalyl chloride.
  • Compounds of formula (IV) wherein R2 and R16 are as hereinbefore defined, Z1 is CH2, L1 is as defined hereinbefore (except where L1 contains a non-aromatic carbon-carbon multiple bond) and A1 is an ethylene linkage, may be prepared by hydrogenation of the corresponding quinoline analogues of formula (2):-
    Figure imgb0270
     wherein R2 and R16 are as hereinbefore defined and L1 is as defined immediately hereinbefore, in the presence of a suitable metal catalyst. The reduction may conveniently be carried out at a pressure of 50 bars of hydrogen, in the presence of 5% rhodium in carbon powder as catalyst, in hydrochloric acid, and at a temperature at about room temperature.
  • Compounds of formula (2), wherein R2 and R16 are as hereinbefore defined and L1 is alkylene may be prepared by an electrochemical coupling reaction between a compound of formula (3):-
    Figure imgb0271
     wherein R2 is as hereinbefore defined and X5 is iodo, or preferably bromo, and an alkenoic ester of formula (X) wherein R16 is as hereinbefore defined and R20 is alkenyl. The reaction may conveniently be carried out in the presence of nickel salt catalyst, such as nickel bromide trihydrate, tetrabutylammonium bromide, tetrabutylammonium iodide and 1,2-dibromoethane, in an inert solvent, or a mixture of inert solvents, such as dimethylformamide and pyridine, and at a temperature at about 60°C. This reaction is particularly suitable for the preparation of compounds of formula (1) in which L1 is ethylene.
  • Compounds of formula (2), wherein R2 and R16 are as defined hereinbefore and L1 is an alkylene linkage substituted by -CH2OR3 (for example -CH2OCH3) may be prepared from compounds of formula (2), wherein R2 and R16 are as defined hereinbefore and L1 is an alkenylene linkage where the carbon-carbon double bond is substituted by a methyl group, using the following standard reaction procedures:- (i) allylic bromination with N-bromosuccinimide; (ii) displacement of the allylic bromo with OR3 by reaction with an alkali metal salt of formula R3O-M+ (for example sodium methoxide); (iii) hydrogenation.
  • Compounds of formula (2), wherein R2 and R16 are as defined hereinbefore and L1 is alkenylene, alkynylene or cycloalkenylene in which the carbon-carbon multiple bond is attached directly to the phenyl moiety in formula (I), may be prepared by reacting a compound of formula (3) wherein R2 is as hereinbefore defined and X5 is an iodine, or preferably a bromine, atom with a compound of formula (X) wherein R16 and R19 are as hereinbefore defined using standard Heck coupling reaction conditions, for example reaction in the presence of palladium acetate, triphenylphosphine and tributylamine at a temperature up to about 120°C.
  • Compounds of formula (2), wherein R2 and R16 are as defined hereinbefore and L1 is an optionally substituted arylene or an optionally substituted heteroaryldiyl linkage, may be prepared by reacting a compound of formula (3) wherein R2 is as hereinbefore defined and X5 is iodo or bromo with a compound of formula (4):-

            Br-L1-CO2R16     (4)

    wherein R16 are as defined hereinbefore and L1 is an optionally substituted arylene or an optionally substituted heteroaryldiyl linkage in the presence of a complex metal catalyst such as tetrakis(triphenylphosphine)palladium(0), using standard reaction conditions, for example those described by Trecourt et al, Tetrahedron, 51 (1995) 43, pages11743-11750.
  • Compounds of formula (IV) or (2) wherein R2 and R16 are as defined hereinbefore and L1 is
    Figure imgb0272
     may be prepared by standard methodology for the preparation of α-aminoacids for example those described in Organic Syntheses Based On Name Reactions and Unnamed Reactions, A.Hassner and C.Stumer, Pergamon, pages 275 and 374.
  • Compounds of formula (2) wherein R2 and R16 are as defined hereinbefore and L1 is
    Figure imgb0273
     may be prepared by reaction of compounds of formula (5):-
    Figure imgb0274
     wherein R2 is as hereinbefore defined and X6 is a bromine or chlorine atom with the anion derived from reaction of (2R) -(-)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine with butyllithium according to the method described by D. L. Boger and D. Yohannes, J. Org. Chem. [JOCEAH], 1990, 55, for the preparation of compound 31 on page 6010.
  • Compounds of formula (IV) wherein R2, R16, A1 and Z1 are as hereinbefore defined and L1 is
    Figure imgb0275
     may be similarly prepared from compounds of formula (6):-
    Figure imgb0276
  • Compounds of formula (6) wherein R2, A1, X6 are as hereinbefore defined and Z1 is CH2 may be prepared by the application or adaptation of methodologies described in US Patent Application No. 4156734, for example the preparation of the N-protected dihydroindole, 1-benzoyl-5-chloromethyl-2,3-dihydro-1H-indole from 1-benzoyl-2,3-dihydro-1H-indole (Beilstein, 20, 257) is described as Example 23A.
  • Compounds of formula (IV) wherein R2, R16 and L1 are as hereinbefore defined, Z1 is CH2, A1 is a straight chain C1-2alkylene linkage and L1 contains an alkenylene, alkynylene or cycloalkenylene group in which the aliphatic carbon-carbon multiple bond is attached directly to the phenyl moiety in formula (IV), may be prepared by coupling of compounds of formula (7)-
    Figure imgb0277
     wherein R2 is as hereinbefore defined, A1 is a straight chain C1-2alkylene linkage, X7 is a halogen, preferably bromine or iodine, atom and Z1 is CH2 with a compound of formula (X) wherein R16 is as hereinbefore defined and R19 is alkenyl, alkynyl or cycloalkenyl. The cross-coupling reaction may conveniently be carried out in the presence of palladium acetate and tris(o-tolyl)phosphine using standard coupling conditions such as those described hereinbefore. In this reaction a suitable protecting group for the NH group is for example a tertiary-butyloxycarbonyl group.
  • Compounds of formula (IV) wherein R2, R16 and L1 are as hereinbefore defined, Z1 is CH2, A1 is a straight chain C1-2alkylene linkage and L1 contains an alkylene or cycloalkylene group may be prepared by hydrogenation of the corresponding compounds of formula (IV) in which L1 contains an alkenylene, alkynylene or cycloalkenylene group using standard hydrogenation procedures for example those described hereinbefore.
  • Compounds of formula (7) wherein R2 is hydrogen, A1 is ethylene, Z1 is CH2 and X6 is an iodine atom attached to the 6 position of the tetrahydroquinoline ring may be prepared by iodination of 1,2,3,4-tetrahydroquinoline with iodine monochloride in acetic acid at a temperature at about room temperature.
  • 2,3-Dihydro-4(1H)-quinolones of formula (7) wherein R2 is hydrogen, A1 is ethylene, Z1 is C(=O) and X6 is a halogen atom attached to the 6 position of the tetrahydroquinoline ring may be prepared by the application or adaptation of the Fries-type acid catalysed rearrangement of 1-arylazetidin-2-ones described by S.Kano et. al. J. Chem. Soc., Perkin Trans. 11098,10 pages 2105-2111.
  • Compounds of formula (IV) wherein R2, R16, L1 and A1 are as hereinbefore defined and Z1 is CH2, and L1 is a
    Figure imgb0278
     linkage, may be prepared by reacting an ester of formula (I), wherein R1, R2 and A1 are as hereinbefore defined, Y is a -CO2R16 group (in which R16 is as hereinbefore defined), Z1 is CH2, and L1 is a -CH=CH- linkage, with dimethyl malonate, in the presence of an alkali metal alkoxide, such as sodium methoxide, in methanol and at a temperature at about reflux temperature.
  • Compounds of formula (IV) wherein R2, R16 and A1 are as hereinbefore defined and Z1 is CH2, and the moiety -L2-Y is
    Figure imgb0279
     may be prepared coupling of compounds of formula (8) wherein R2 and A1 are as hereinbefore defined, and X6 is a halogen, preferably bromine or iodine, atom with 5,6-dihydropyran-2-one in the presence of tetrakis(triphenylphosphine)palladium (0) and triethylamine in an inert solvent, such as dimethylformamide, at a temperature at about 95°C and in a sealed vessel.
  • Compounds of formula (IV) wherein R2, R16, L1 and A1 are as hereinbefore defined and Z1 is CH2, and L1 contains a -N(R8)-C(=O)-R9 group (in which R8 and R9 are as hereinbefore defined) may be prepared from the corresponding compounds of formula (IV) where L1 contains a -NHR8 group (in which R8 is as hereinbefore defined) by reaction with a compound of formula R9-C(=O)-X1 wherein R9 and X1 are as hereinbefore defined, using standard peptide coupling procedures for example those described hereinbefore.
  • Compounds of formula (IV) wherein R1, R2, A1 and Z1 are as hereinbefore defined, Y is a -CO2R16 group (in which R16 is as hereinbefore defined) and L1 is
    Figure imgb0280
     (or
    Figure imgb0281
     may be prepared by hydrogenation of the corresponding derivatives of formula (IV), where L1 is
    Figure imgb0282
     The reaction may be carried out in the presence of formic acid and a suitable metal catalyst, e.g. palladium, supported on an inert carrier such as carbon, at a temperature at about 60°C. The reaction may conveniently be carried out in the presence of a suitable metal catalyst, e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol.
  • Compounds of formula (IV) wherein R1, R2, A1 and Z1 are as hereinbefore defined, Y is a -CO2R16 group (in which R16 is as hereinbefore defined) and L1 is a
    Figure imgb0283
     (or
    Figure imgb0284
     linkage, may also be obtained from the racemic mixture following standard recrystallisation of a suitable salt (for example recrystallisation of the tartrate salt), or by the application of standard enzymatic resolution procedures (for example those described by Soloshonok, V. A., et. al., Tetrahedron: Asymmetry 6 (1995) 7, 1601-1610).
  • Compounds of formula (IV) wherein R1, R2, A1 and Z1 are as hereinbefore defined, Y is a -CO2R16 group (in which R16 is as hereinbefore defined) and L1 is a
    Figure imgb0285
     or
    Figure imgb0286
     linkage, may be prepared by reacting compounds of formula (IV) wherein R1, R2, A1 and Z1 are as hereinbefore defined, Y is a -CO2R16 group (in which R16 is as hereinbefore defined) and L1 is a -CH=CH- linkage, with an alkali metal hydride, such as sodium hydride, in an inert solvent, e.g. tetrahydrofuran, and at a temperature at about room temperature, and subsequent reaction with the anion derived from treating dibenzylamine, or (S)-N-benzyl-α-methylbenzylamine, with butyllithium, at a temperature at about -78°C.
  • Compounds of formula (IX) wherein R1, R2 and X4 are as described hereinbefore, A1 is methylene and Z1 is C(=O) may be prepared by the application or adaptation of methods described by Bourlot, A. S. et. al., Synthesis, 1994,4,411-416.
  • Compounds of formula (IX) wherein R1, R2 and X4 are as described hereinbefore, A1 is ethylene and Z1 is C(=O) may be prepared by the application or adaptation of methods described in United States Patent Application No. US4421918.
  • Intermediates of formulae (IV), (IX) and (2) are novel compounds and, as such, they and processes described herein for their preparation constitute further features of the present invention.
  • The present invention is further Exemplified but not limited by the following illustrative Examples and Reference Examples.
  • In the nuclear magnetic resonance spectra (NMR) the chemical shifts are expressed in ppm relative to tetramethylsilane. Abbreviations have the following significances: s = singlet; d = doublet; t = triplet; m = multiplet.
  • Mass spectra (MS) for Example 4(b) and for the Reference Examples (unless otherwise indicated) were recorded on a Micromass Platform II mass spectrometer fitted with an Electrospray source and an HP1100 liquid chromatograph; using a mixture of acetonitrile and water (1:1, v/v) as the mobile phase, a flow rate of 0.3 ml/minute, an injection volume of 20µl, a run time of 2.0 minutes, a scan range of 150 - 850 Daltons Positive/Negative, a scan time of 2.0 seconds, an ESI voltage of 3.5Kv, an ESI pressure of 20n/m2 Nitrogen. Mass spectra [MS(ES+)] for the Examples 1 - 12 were recorded on a Micromass LCT Mass Spectrometer (Orthogonal Acceleration Time of Flight Mass Spectrometer), with the Z-Flow Atmospheric pressure ionisation source operating in positive ion electrospray mode (ES+), connected to an HP1100 liquid chromatograph. The conditions used were as follows: 3 micron Luna C18 HPLC column (30mm x 4.6mm) operated under gradient elution conditions with a mixture of acetonitrile and water as the mobile phase gradient: 0.00 minutes, 95% water:5% acetonitrile; 0.50 minutes, 95% water:5% acetonitrile; 4.50 minutes, 5% water:95% acetonitrile; 5.00 minutes, 5 % water :95 % acetonitrile; 5.50 minutes, 95 % water :5% acetonitrile; flow rate 2ml/minutewith approximately 200ml/minute split to the Mass Spectrometer; injection volume 10-40ml; in line Diode Array detection (220-450nm), in line Evaporative light scattering (ELS) detection ELS - temperature 50°C, Gain 8 - 1.8ml/minute; Source temperature 150°C.
    • EXAMPLE 1 3-(1-{[3-Methoxy-4-(3-[2-methylphenyl]-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid
  • A solution of ethyl 3-(1-{[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl}acetyl)-1,2,3,4-tetrahydroquinolin-6-yl)-propanoate (0.24g, Reference Example 1) in anhydrous ethanol (4ml), at 20°C, was treated dropwise with a solution of lithium hydroxide monohydrate (33mg) in distilled water (1ml). After stirring for 3 hours at 20°C the reaction mixture was evaporated under reduced pressure (2.7 kPa) at 40°C. The residue was treated with distilled water (35ml) and the resulting solution was washed twice with diethyl ether (20ml), then acidified to pH 3 by addition of hydrochloric acid (0.8ml, 1N) and then extracted twice with ethyl acetate (25ml). The combined organic extracts were washed twice with water (5ml), then dried over magnesium sulfate and then evaporated under reduced pressure (2.7 kPa) at 40°C. The resulting white foamy solid (191mg) was subjected to chromatography on silica gel plates (4 plates, 20x20cm, thickness = 0.5mm), eluting with a mixture of dichloromethane and methanol (9:1, v/v) to give the title compound (148mg) as a white foamy solid. 1H NMR (300 MHz, (CD3)2SO): δ 1.81 (m, 2H); 2.27 (s, 3H); from 2.45-2.70 (m, 4H), 2.82 (t, J=7.5Hz, 2H); 3.72 (t, J=6.5Hz, 2H); 3.82 (s, 2H); 3.87 (s, 3H); 6.60-7.50 (m, 8H); 7.82 (d, J= 8 Hz, 1H); 8.05 (d, J= 8 Hz, 1H); 8.50 (s, 1H); 8.60 (s, 1H). MS (Electron Impact recorded on a Finnigan SSQ 7000 spectrometer at70eV) 501(M+).
    • EXAMPLE 2
    • (a) (R/S) 3-(1-{[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-butyric acid
      A solution of ethyl (R/S) 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-butyrate [2.8g, Reference Example 4(a)] in methanol (about 150ml) was treated with aqueous sodium hydroxide solution (15ml, 1M). The mixture was warmed at about 50°C for 3 hours, then treated with a further aliquot of aqueous sodium hydroxide solution (7.5ml). After a further 2-3 hours at 50°C TLC analysis indicated complete reaction. The bulk of the methanol was removed by evaporation and the residue was diluted with hydrochloric acid (about 200ml, 1M). The resulting mixture was stirred for about 30 minutes, then the solid was collected by filtration, washed with water, and dried to give the title compound (2.3g) as a very light orange powder. LC-MS: RT = 3.84 minutes (100% total area by ELS); MS(ES+) 502 (MH+), 524 (MNa+).
    • (b) By proceeding in a similar manner to Example 2(a) but using ethyl (R/S) 3-{1-[(2-o-tolylamino-3H-benzimidazol-5-yl)-acetyl]-1,2,3,4-tetrahydro-quinolin-6-yl}-butyrate [Reference Example 4(k)] and carrying out the hydrolysis at room temperature there was prepared (R/S) 3-{1-[(2-o-tolylamino-3H-benzimidazol-5-yl)-acetyl]-1,2,3,4-tetrahydro-quinolin-6-yl}-butyric acid as a white solid. [Elemental analysis:- C, 71.11; H, 6.55; N, 8.66%. Calculated for C30H31N3O4•0.5H2O:- C, 71.15; H, 6.32; N, 8.30%]. MS (ES+) 498 (MH+).
    • (c) By proceeding in a similar manner to Example 2(a) but using a suspension of ethyl (R/S) 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-heptanoate [Reference Example 4(p)] in industrial methylated spirits and carrying out the reaction at 80°C for 45 minutes there was prepared (R/S) 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl} 2.3-dihydro-1H-indol-5-yl)-heptanoic acid as a white solid. LC-MS (using 0.1 v/v formic acid in acetonitrile to replace acetonitrile for the gradient elution): RT=4.31 minutes (100% total area by ELS); MS(ES+) 544(MH+), 566(MNa+).
    • (d) By proceeding in a similar manner to Example 2(a) but using ethyl (R/S) 3-[-({4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetyl)-2,3-dihydro-1H-indol-5-yl]-heptanoate [Reference Example 4(q)] in industrial methylated spirits and carrying out the reaction at 80°C for 45 minutes there was prepared (R/S) 3-[-({4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetyl)-2,3-dihydro-1H-indol-5-yl]-heptanoic acid as a white powder. LC-MS (using 0.1 v/v formic acid in acetonitrile to replace acetonitrile for the gradient elution): RT=4.47 minutes (100% total area by ELS); MS(ES+) 556(MH+), 578(MNa+).
    • (e) By proceeding in a similar manner to Example 2(a) but using ethyl (R/S) 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-pentanoate [Reference Example 4(r)] and carrying out the reaction at reflux temperature for 1 hour there was prepared (R/S) 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-pentanoic acid as a pale fawn solid. LC-MS: RT=3.01 minutes; MS(ES+) 538 (MNa+).
    • (f) By proceeding in a similar manner to Example 2(a) but using ethyl (R/S) 3-[-({4-[(2,3. dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetyl)-2,3-dihydro-1H-indol-5-yl]-pentanoate [Reference Example 4(s)] in industrial methylated spirits and carrying out the reaction at 80°C for 45 minutes there was prepared (R/S) 3-[-({4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetyl)-2,3-dihydro-1H-indol-5-yl]-pentanoic acid as a white powder. LC-MS (using 0.1 v/v formic acid in acetonitrile to replace acetonitrile for the gradient elution): RT=4.17 minutes (100% total area by ELS) ; MS(ES+) 528(MH+), 550(MNa+).
    • (g) By proceeding in a similar manner to Example 2(a) but using ethyl (R/S) 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-3-phenyl-propionate [Reference Example 4(s)] and carrying out the reaction at reflux temperature for 1 hour there was prepared (R/S) 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl]-2,3-dihydro-1H-indol-5-yl)-3-phenyl-propionic acid as an off-white solid. LC-MS: RT=3.17 minutes; MS(ES+) 564 (MH+), 586 (MNa+).
    • (h) By proceeding in a similar manner to Example 2(a) but using R/S ethyl 3-[-({4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetyl)-2,3-dihydro-1H-indol-5-yl]-3-phenyl-propionate [Reference Example 4(u)] in industrial methylated spirits and carrying out the reaction at 80°C for 90 minutes there was prepared (R/S) 3-[-({4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetyl)-2,3-dihydro-1H-indol-5-yl]-3-phenyl-propionic acid as an off-white powder. LC-MS (using 0.1 v/v formic acid in acetonitrile to replace acetonitrile for the gradient elution): RT=4.27 minutes (100% total area by ELS); MS(ES+) 576(MH+), 598(MNa+).
    EXAMPLE 3
    • (a) (R/S) 3-(1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-butyric acid A mixture of ethyl (R/S) 3-(1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-butyrate [0.55g, Reference Example 4(b)], aqueous sodium hydroxide solution (5.5ml, 1M), methanol (5.5ml) and tetrahydrofuran (11ml) was stirred at room temperature overnight then evaporated to low bulk. The residue was diluted with water and the mixture was acidified by the addition of hydrochloric acid. The precipitate was collected by filtration, washed with water and then dried to give the title compound (0.41g) as a white powder. LC-MS: RT = 3.77 minutes (100% total area by ELS); MS(ES+) 472 (MH+), 494 (MNa+).
    • (b) By proceeding in a similar manner to Example 3(a) but using ethyl (R/S) 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)- butyrate [Reference Example 4(e)] there was prepared (R/S) 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-butyric acid as a white powder. LC-MS: RT = 3.89 minutes (100% total area by ELS); MS(ES+) 516(MH+), 538 (MNa+).
    • (c) By proceeding in a similar manner to Example 3(a) but using ethyl (R/S) 3-(1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-butyrate [Reference Example 4(f)] there was prepared (R/S) 3-(1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-butyric acid as a white solid. LC-MS: RT = 2.92 minutes (100% total area by ELS); MS(ES+) 508 (MNa+).
    • (d) By proceeding in a similar manner to Example 3(a) but using ethyl (R/S) 3-{1-[(2-o-tolylamino-benzoxazol-6-yl)-acetyl]-1,2,3,4-tetrahydro-quinolin-6-yl}-butyrate [Reference Example 4(g)] there was prepared (R/S) 3-{1-[(2-o-tolylamino-benzoxazol-6-yl)-acetyl]-1,2,3,4-tetrahydro-quinolin-6-yl}-butyric acid as a colourless foam. LC-MS: RT = 3.01 minutes (100% total area by ELS); MS(ES+) 484 (MH+), 506 (MNa+).
    EXAMPLE 4
    • (a) 3-(1-{[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-pentanedioic acid
      A stirred suspension of dimethyl -3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-pentanedioate [270mg, Reference Example 4(c)] in ethanol (10ml) was treated with a solution of sodium hydroxide (190mg) in water (2ml) and the mixture stirred at reflux for 3 hours. After cooling to room temperature the mixture was treated with water (10ml) and then carefully acidified to pH1 by the addition of hydrochloric acid (3M) with ice cooling. The resultant precipitate was collected by filtration, then dried and then recrystallised from ethyl acetate to give the title compound (60mg) as a white crystalline solid. LC-MS: RT = 2.44 minutes (100% total area by ELS); MS(ES+) 568 (MNa+).
    • (b) By proceeding in a similar manner to Example 4(a) but using dimethyl 3-(1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-pentanedioate [Reference Example 4(d)] there was prepared 3-(1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-pentanedioic acid as a white solid. MS (ES-) 514 (M-).
    • (c) By proceeding in a similar manner to Example 4(a) but using dimethyl 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-pentanedioate [Reference Example 4(h)] and subjecting the product to flash chromatography on silica eluting with a mixture of methanol and dichloromethane (1:9, v/v) there was prepared 3-(1-{[3-methoxy-4-(3-o-tolyl-ureidol-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-pentanedioic acid as a white foam. LC-MS: RT = 2.40 minutes (100% total area by ELS); MS(ES+) 582 (MNa+).
    • (d) By proceeding in a similar manner to Example 4(a) but using methyl (R) 4-[2-methoxycarbonyl-1-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-ethylcarbamoyl]-butyrate [Reference Example 4(i)] and subjecting the product to flash chromatography on silica eluting with a mixture of methanol and dichloromethane (1:9, v/v) there was prepared (R) 4-[2-carboxy-1-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-ethylcarbamoyl]-butyric acid as a white powder. LC-MS: RT = 2.43 minutes (100% total area by ELS); MS(ES+) 653 (MNa+).
    • (e) By proceeding in a similar manner to Example 4(a) but using methyl (R) N-[2-methoxycarbonyl-1-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydroquinolin-6-yl)-ethyl]-succinamate [Reference Example 4(j)] and subjecting the product to flash chromatography on silica eluting with a mixture of methanol and dichloromethane (1:9, v/v) there was prepared (R) N-[2-carboxy-1-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-succinamic acid as a colourless gum. LC-MS: RT = 2.44 minutes (100% total area by ELS); MS(ES+) 639 (MNa+).
    EXAMPLE 5 (R/S) 1-(4-(2-Oxo-2-[6-(2-oxo-tetrahydro-pyran-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-ethyl]-phenyl)-3-o-tolyl-urea
  • A solution of {4-(3-o-tolyl-ureido)-phenyl}-acetic acid (310mg) and diisopropylethylamine (310mg) dimethylformamide (5ml) was treated successively with O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (450mg), then (R/S) 4-(1,2,3,4-tetrahydro-quinolin-6-yl)-tetrahydro-pyran-2-one [250mg, Reference Example 5(c)]. After standing at room temperature for 2 hours the mixture was partitioned between ethyl acetate (100ml) and dilute hydrochloric acid (100ml). The layers were separated and the organic layer was washed with water, dried and evaporated. The residue was subjected to flash chromatography on silica eluting with ethyl acetate to give a yellow gum. This was dissolved in the minimum volume of ethanol and the solution was then treated with ether to yield a yellow solid, which was collected by filtration and dried to give the title compound (80mg) as a yellow solid. LC-MS: RT = 3.74 minutes (100% total area by ELS); MS(ES+) 520 (MNa+).
    • EXAMPLE 6 (R) 3-(1-{[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-3-[(5-methyl-isoxazole-3-carbonyl)-amino]-propionic acid
  • Methyl (R) 3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)-3-[(5-methyl-isoxazole-3-carbonyl)-amino]-propionate [310mg, Reference Example 17] was dissolved in a mixture of trifluoroacetic acid and dichloromethane (1:3, v/v) and the clear solution allowed to stand at room temperature for 2 hours. The residue obtained on evaporation of this solution was added to a mixture of [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid (280mg), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (340mg) and diisopropylethylamine (1ml) in dimethylformamide (30ml). The resultant mixture was stirred at room temperature for 3 hours and then allowed to stand overnight. The mixture was evaporated to low bulk and the residue was partitioned between ethyl acetate and dilute hydrochloric acid. The layers were separated and the organic layer was washed with sodium carbonate solution, dried and evaporated to give 580mg of an orange oil. Purification by flash chromatography eluting with 1:1 ethyl acetate and dichloromethane gave an orange foam. This product was dissolved in methanol (20ml) and the solution treated with 1.0 M sodium hydroxide solution. After refluxing for 2 hours the mixture was evaporated to low bulk and the residue diluted with water. Acidification with dilute hydrochloric acid gave a gummy product which was extracted into ethyl acetate solution. This solution was dried and evaporated to give the title compound (110mg) as a light yellow foam. LC-MS: RT = 2.94 minutes (100% total area by ELS); MS(ES+) 648 (MNa+).
    • EXAMPLE 7
    • (a) (S) 2-(2-Chloro-6-methyl-benzoylamino)-3-[1-(2,6-dichloro-benzoyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-propionic acid
      A mixture of methyl (S) 2-amino-3-[1-(2,6-dichloro-benzoyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-propionate (200mg, Reference Example 18), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (200mg) and 2-chloro-6-methylbenzoic acid (90mg) in dimethylformamide was treated with diisopropylethylamine (150mg) and the clear solution allowed to stand at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (50ml) and dilute hydrochloric acid (50ml). The organic phase was washed with sodium bicarbonate solution, then dried and then evaporated. The residue was examined by Thin Layer Chromatography on silica using a mixture of ethyl acetate and dichloromethane (1:9, v/v) and showed two very close spots, of approximately equal intensity. The product was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and dichloromethane (1:9, v/v): the bulk of the fractions contained mixed spots, but separate fractions containing each of the pure components was obtained. On standing in solution for more than about one hour, each pure component reverted to an identical mixture of the two components, suggesting that the two spots represented stable rotamers. Accordingly, all fractions containing either or both spots were combined and evaporated to give a colourless oil (160mg). This material was dissolved in methanol (10ml) and treated with lithium hydroxide solution (4mt, 1M). After standing at room temperature for 30 minutes the mixture was evaporated to low bulk and the residue dissolved in water (10ml). Acidification with dilute hydrochloric acid afforded a white precipitate, which was collected by filtration, washed with water and then dried to give the title compound (105mg) as a white solid. LC-MS: (indicated a mixture of two stable rotamers): rotamer 1, RT = 2.79 minutes (57% total area by ELS), MS (ES+) 567, 569 (MNa+); rotamer 2, RT = 3.96 minutes (43% total area by ELS), MS (ES+) 567, 569 (MNa+).
    • (b) By proceeding in a similar manner to Example 7(a) but using tetrahydro-pyran-4-carboxylic acid there was prepared (S) 3-[1-(2,6-dichloro-benzoyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-2-[(tetrahydro-pyran-4-carbonyl)-amino]-propionic acid as a white powder. LC-MS: (indicated a mixture of two stable rotamers): rotamer 1, RT = 2.47 minutes (52% total area by ELSD), MS (ES+) 527 and 529 (MNa+); rotamer 2, RT = 2.66 minutes (48% total area by ELS), MS (ES+) 527 and 529 (MNa+).
    EXAMPLE 8 (S) 2-(2 6-Dichloro-benzoylamino)-3-[1-(2,6-dichloro-benzoyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-propionic acid
  • A solution of methyl (S) 2-amino-3-[1-(2,6-dichloro-benzoyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-propionate (180mg, reference Example 18) in dichloromethane (10ml) was treated with diisopropylethylamine (150mg) then with 2,6-dichlorobenzoyl chloride (130mg). After standing at room temperature overnight the mixture was partitioned between ethyl acetate (50ml) and dilute hydrochloric acid (50ml). The organic phase was washed with sodium bicarbonate solution, then dried and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and dichloromethane (1:9, v/v) to give a colourless oil (160mg). This material was treated with methanol (10ml) and then with lithium hydroxide solution (4ml, 1M). After standing at room temperature for one hour the mixture was evaporated to low bulk and the residue was dissolved in water (10ml). The solution was acidification by addition of dilute hydrochloric. The resulting white precipitate was filtered then washed with water and then dried to give the title compound (120mg) as a white solid. LC-MS (indicated a mixture of stable rotamers): rotamer 1, RT = 2.79 minutes (48% total area by ELS), MS (ES+) 587, 599 (MNa+); rotamer 2, RT = 3.74 minutes (10 total area by ELS), MS (ES+) 587, 589 (MNa+); rotamer 3, RT = 3.96 minutes (46% total area by ELS), MS (ES+) 587, 599 (MNa+).
    • EXAMPLE 9 (R/S) 3-[1-({4-[(2,3-Dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-butyric acid
    • Step 1. Bromo-Wang resin (1g, nominal loading of 1 mmol/g, Novabiochem) was suspended in dimethylformamide (15ml) and treated successively with a solution of (R/S) 6-(2-carboxy-1-methyl-ethyl)-3,4-dihydro-2H-quinoline-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (880mg, Reference Example 28) in dimethylformamide (5ml), diisopropylethylamine (0.35ml) and cesium iodide (270mg). The mixture was allowed to stand at room temperature with occasional shaking overnight. The resin was drained then washed (i) five times with dimethylformamide, (ii) three times with water, (iii) three times with dimethylformamide, (iv) three times with methanol, (v) four times with dichloromethane, and (vi) twice with ether, and then dried.
    • Step 2. The resin from Step 1 was then suspended in a mixture of piperidine and dimethylformamide (20ml, 1:4, v/v) and the mixture was kept at room temperature with occasional shaking for about 2 hours. The resin was drained then washed (i) five times with dimethylformamide, (ii) three times with methanol, (iii) four times with dimethylformamide, and (vi) twice with ether, and then dried.
    • Step 3. The resin from Step 2 was then suspended in dimethylformamide (15ml) and treated successively with O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (570mg), {4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetic acid (490mg) and diisopropylethylamine (0.52ml) and the mixture allowed to stand at room temperature with occasional shaking overnight. The resin was drained washed then washed (i) five times with dimethylformamide, (ii) three times with methanol, (iii) four times with dimethylformamide, and (vi) twice with ether, and then dried.
    • Step 4. The resin from Step 3 was treated with a mixture of trifluoroacetic acid and dichloromethane (about 10ml, 1:1, v/v) and the mixture kept at room temperature with occasional shaking for about 1 hour. The resin was drained and then washed with a mixture of trifluoroacetic acid and dichloromethane (about 1ml, 1:1, v/v). The combined filtrates were evaporated and the residual brown oil was treated with dilute sodium hydroxide solution. The resulting aqueous solution was washed with ether, then with dichloromethane, and then acidified by addition of hydrochloric acid. The precipitated product was extracted four times with dichloromethane. The combined extracts were dried and then evaporated. The residue was triturated with ether to give the title compound (120mg) as a cream solid. LC-MS: RT = 3.16 minutes (100% total area by ELS); MS(ES+) 550 (MNa+).
    EXAMPLE 10 (S) 2-Acetylamino-3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid
  • A solution of methyl (S) 2-acetylamino-3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl)-1,2,3,4-tetrahydro-quinolin-6-yl)-propionate [220mg, Reference Example 4(1)] in dioxane (3ml) was treated with a solution of lithium hydroxide hydrate (50mg) in water (1ml). The mixture was stirred at room temperature for 3 hours, then treated with water (5ml), then acidified to pH 1-2 by the addition of dilute hydrochloric acid (with ice cooling). The resulting precipitate was extracted three times with ethyl acetate and the combined extracts were washed with water, then with brine, then dried and then evaporated. The residue was recrystallised from ethyl acetate to give the title compound (21mg)as a white powder. LC-MS: RT = 2.77 minutes (100% total area by ELS); MS(ES+) 581 (MNa+).
    • EXAMPLE 11 (R/S) 3-(1-{[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-butyric acid, sodium salt.
  • A solution of (R/S) 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-butyric acid (2.1g) in methanol (about 150ml) was treated with exactly one equivalent of 0.1M sodium hydroxide solution. The methanol was evaporated off and the residue diluted with water (about 120ml) and lyophilised. The lyophilate was triturated with ether and the insoluble material was then washed with ether, then with pentane and then dried to give the title compound (1.9g) as an off-white, free-flowing powder. MS(ES+) 525 (MH+). [Elemental analysis : Found: C, 60.01; H, 6.13; N, 7.28; H2O, 8.25%. Calculated for C29H30N3NaO5•0.3H2O: C, 60.25; H, 6.20; N, 7.27; H2O, 9.3 %].
    • EXAMPLE 12
    • (a) (S) 2-(2,6-Dichloro-benzoylamino)-3-{1-[(2-o-tolylamino-benzoxazol-6-yl)-acetyl]-1,2,3,4--tetrahydro-quinolin-6-yl}-propionic acid
      Methyl (S) 2-(N-boc-amino)-3-{1-[(2-o-tolylamino-benzoxazol-6-yl)-acetyl]-1,2,3,4-tetrahydroquinolin-6-yl}-propionate [200mg, Reference Example 4(m)] was treated with trifluoroacetic acid (3ml) and the resulting solution was left at room temperature for 15 minutes then evaporated. The residue was dissolved in dichloromethane (20ml) and treated with diisopropylethylamine (260 mg) and then with 2,6-dichlorobenzoyl chloride (140mg). After standing at room temperature overnight the mixture was evaporated to low bulk and the residue partitioned between ethyl acetate (50ml) and dilute hydrochloric acid. The organic phase was washed with sodium bicarbonate solution, then dried and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and dichloromethane (15:85 .v/v). The resulting colourless gum was treated with methanol (10ml) and then with lithium hydroxide solution (2ml,1M). After standing at room temperature for 2 hours the mixture was evaporated to low bulk, the residue was treated with water (10ml) and the mixture acidified by addition of dilute hydrochloric acid. The resulting white precipitate was filtered, then washed with water, and then dried to give the title compound (90mg) as a white powder. LC-MS: RT = 2.97 minutes (100% total area by ELS); MS(ES+) 657 and 659 (MH+) 679 and 681 (MNa+).
    • (b) By proceeding in a similar manner to Example 12(a) but using methyl (S) 3-[1-(2-chlorobenzoyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-2-(N-boc-amino)-propionate [Reference Example 4(n)] and 2-chloro-6-methylbenzoyl chloride there was prepared (S) 3-[1-(2-chloro-benzoyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-2-(2-chloro-6-methyl-benzoylamino)-propionic acid as a white powder. LC-MS: RT = 2.76 minutes (100% total area by ELS); MS (ES+) 533 and 535 (MNa+).
    • (c) By proceeding in a similar manner to Example 12(a) but using methyl (S) 3-{1-[(4-acetoxy-3-chloro-phenyl)-acetyl]-1,2,3,4-tetrahydro-quinolin-6-yl}-2-(N-boc-amino)-propionate [Reference Example 4(o)] and 2-chloro-6-methylbenzoyl chloride-there was prepared (S) 3-{1-[(3-chloro-4-hydroxy-phenyl)-acetyl]-1,2,3,4-tetrahydro-quinolin-6-yl]-2-(2-chloro-6-methyl-benzoylamino)-propionic acid. LC-MS: RT = 2.67 minutes (100% total area by ELS); MS (ES+) 563 and 565 (MNa+).
    REFERENCE EXAMPLE 1 Ethyl 3-[1-(2-{3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl}acetyl)-1,2,3,4-tetrahydro-6-quinolinyl]propanoate
  • A stirred solution of 3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetic acid (0.232g, prepared as described in Example 52B of International Patent Application Publication No. WO 96/22966) in anhydrous tetrahydrofuran (5ml), under an atmosphere of argon and at 20°C, was treated with powdered molecular sieves 4Å (2g), ethyl 3-(1,2,3,4-tetrahydro-6-quinolinyl)propanoate (0.115g, Reference Example 2), triethylamine(0.275ml), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.223g) and 4-dimethylaminopyridine (6mg). After stirring at 20°C for 1 hour the reaction mixture was filtered through a pad of celite. The filtrate was evaporated under reduced pressure (2.7 kPa) at 40°C and the residue was treated with ethyl acetate (25ml). The solution obtained was washed twice with saturated aqueous ammonium chloride solution (5ml), then with water (5ml), then dried over magnesium sulfate, and then evaporated under reduced pressure (2.7 kPa) at 40°C. The resulting white foamy solid (0.457g) was subjected to flash chromatography on silica (0,040-0,063mm) eluting with a mixture of cyclohexane and ethyl acetate (250ml, 9:1, then 500ml, 7:3, then 1000ml, 4:6; v/v) to give the title compound (0.244g) as a white foamy solid.
    • REFERENCE EXAMPLE 2 Ethyl 3-(1,2,3,4-tetrahydro-6-quinolinyl)propanoate
  • A stirred mixture of ethyl 3-(6-quinolinyl)propanoate (0.3g, Reference Example 3) in hydrochloric acid (3ml, 0.1N) and 5% rhodium in carbon powder (33mg) was hydrogenated in a 22 cm3 stainless steel pressure reactor at a pressure of 50 bars of hydrogen. After stirring for 4 hours at 25°C a further portion of 30 mg of 5% rhodium in carbon powder (33mg) was added and the hydrogenation was continued under a pressure of 50 bars at 25°C for 1 hour. The reaction mixture was filtered through a pad of celite and the filter pad was washed with hydrochloric acid (3ml, 0.1N) then with ethyl acetate (25ml). The combined filtrate and washings were combined and the aqueous phase was decanted from the organic phase. The aqueous phase was extracted twice with ethyl acetate (25ml) and combined with the aforementioned organic phase. The combined solutions were dried over magnesium sulfate then evaporated under reduced pressure (2. kPa) at 40°C to give the title compound (0.121g) as a brown oil.
    • REFERENCE EXAMPLE 3 Ethyl 3-(6-quinolinyl)propanoate
  • Into the electrochemical apparatus described below were introduced successively, dimethylformamide (45ml), pyridine (5ml), tetrabutylammonium bromide (250mg), tetrabutylammonium iodide (18.8mg) and 1,2-dibromoethane (0.15ml). The solution was deoxygenated by bubbling argon through the solution for about 10 minutes. After carrying out a pre-electrolysis, constant current of 125mA during 30 minutes, the stirred mixture was treated with nickel bromide trihydrate (341mg), 6-bromoquinoline (2.6g), and ethyl acrylate (3.12g). Stirring was continued until complete dissolution. The reaction medium was heated to 60°C and then electrolysis was carried out using a constant current of 250mA whilst maintaining the temperature at 60°C. After 3 hours and the passage of 2810 coulombs (i.e. 2.33 Faradays per mole of 6-bromoquinoline) the electrolysis was stopped. The electrolysed solution plus dimethylformamide washings (20ml) from the electrochemical apparatus and the electrodes was treated with water (250ml) and then extracted three times with heptane (70ml), ethyl acetate (50ml) and diethyl ether (50ml). The combined extracts were evaporated under reduced pressure (2.7 kPa) at 40°C. The residual yellow oil (2.78g) was subjected to Pressure Column Chromatography on silica [40 mm diameter column containing 100 g of silica 60 Merck (0,040-0,063 mm)] eluting with a mixture of cyclohexane, ethyl acetate and 2-propanol (90:8:2 then 85/12/3; v/v/v) under a slight pressure of argon (approximately 30 Kpa) to give the title compound (1.92g) as a yellowish oil.
  • The electrochemical apparatus is made up of: a cylindrical body (50ml volume) which contains the reaction medium and into which is plunged a 10 mm diameter soft iron bar (the consumable anode) and a cylindrical nickel foam grid (diameter 30mm, height 42.5mm, surfaces connect approximately 40ml) concentrically laid out around the anode; a glass lid provided with 5 threaded outputs; a central output for the electrical contact of the anode; four peripheral outputs for the electrical contact of the cathode, thermometer, tubing for argon arrival and a cooling agent with water. The two parts of the electrolyser are associated by the intermediate of a 60 mm interior diameter flat grinding, ensuring the sealing. The reaction medium is maintained under an inert atmosphere by continuously bubbling argon through the electrolysed solution. The electrodes are connected to a stabilized power supply or an intentiostat. Moreover, in the circuit of the anode, a current integrator is connected in series. The reaction medium is stirred by a Teflon® covered magnet bar. The body of the electrochemical apparatus can be plunged in an oil bath at the required temperature for the reaction.
    • REFERENCE EXAMPLE 4
    • (a) Ethyl (R/S) 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-butyrate
      A solution of [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid (2.9g) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.7g) in dimethylformamide (about 40ml) was treated with diisopropylethylamine (10ml), followed after about 30 seconds by a solution of (R/S) ethyl 3-(2,3-dihydro-1H-indol-5-yl)butyrate [about 2.5g, Reference Example 5(a)] in dimethylformamide (about 10ml). The resulting clear, dark brown solution was kept at room temperature for about one hour then evaporated to low bulk. The residue was partitioned between water and ethyl acetate and the organic layer was washed with dilute hydrochloric acid, then with aqueous sodium bicarbonate solution, then with brine, then dried and then evaporated. The residual brown gum was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and petrol (3:2 to 3:1, v/v) to give the title compound (2.8g) as a light yellow, amorphous foam. MS(ES+) 552 (M-Na+).
    • (b) By proceeding in a similar manner to Reference Example 4(a) but coupling [4-(3-o-tolyl-ureido)-phenyl]-acetic acid with (R/S) ethyl 3-(2,3-dihydro-1H-indol-5-yl)butyrate there was prepared ethyl (R/S)3-(1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-butyrate as an off-white solid. MS(ES+) 500 (MH+), 522 (MNa+). MS(ES-) 498 (M-).
    • (c) By proceeding in a similar manner to Reference Example 4(a) but coupling [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid with dimethyl 2-(2,3-dihydro-1H-indol-5-ylmethyl)-pentanedioate (Reference Example 9) there was prepared dimethyl 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-pentanedioate as an off-white foam. MS(ES+) 574 (MH+), 596 (MNa+).
    • (d) By proceeding in a similar manner to Reference Example 4(a) but coupling [4-(3-o-tolyl-ureido)-phenyl]-acetic acid with dimethyl 2-(2,3-dihydro-1H-indol-5-ylmethyl)-pentanedioate (Reference Example 9) there was prepared dimethyl 3-(1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-pentanedioate as a white foam. MS(ES+) 566 (MNa+). MS(ES-) 542 (M-).
    • (e) By proceeding in a similar manner to Reference Example 4(a) but coupling [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid with ethyl (R/S) 3-(1,2,3,4-tetrahydro-quinolin-6-yl)butyrate [Reference Example 5(b)] there was prepared ethyl (R/S) 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-butyrate as a yellow gum. MS(ES+) 544 (MH+), 566 (MNa+). MS(ES-) 542 (M-).
    • (f) By proceeding in a similar manner to Reference Example 4(a) but coupling [4-(3-o-tolyl-ureido)-phenyl]-acetic acid with ethyl (R/S) 3-(1,2,3,4-tetrahydro-quinolin-6-yl)butyrate [Reference Example 5(b)] there was prepared ethyl (R/S) 3-(1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-butyrate.
    • (g) By proceeding in a similar manner to Reference Example 4(a) but coupling (2-o-tolylamino-benzoxazol-6-yl)-acetic acid with ethyl (R/S) 3-(1,2,3,4-tetrahydro-quinolin-6-yl)butyrate [Reference Example 5(b)] there was prepared ethyl (R/S) 3-{1-[(2-o-tolylamino-benzoxazol-6-yl)-acetyl]-1,2,3,4-tetrahydro-quinolin-6-yl}-butyrate.
    • (h) By proceeding in a similar manner to Reference Example 4(a) but coupling [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid with dimethyl 3-(1,2,3,4-tetrahydro-quinolin-6-yl)-pentanedioate [Reference Example 9(b)] and subjecting the product to flash chromatography on silica eluting with a mixture of ethyl acetate and petrol (3:1, v/v) there was prepared dimethyl 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-pentanedioate as an off-white foam. MS(ES+) 588 (MH+), 610 (MNa+). MS(ES-) 586 (M-).
    • (i) By proceeding in a similar manner to Reference Example 4(a) but coupling [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid with methyl (R) 4-[1-(1,2,3,4-tetrahydro-quinolin-6-yl)-2-methoxycarbonyl-ethylcarbamoyl]-butyrate [Reference Example 13(a)] and subjecting the product to flash chromatography on silica eluting with a mixture of methanol and dichloromethane (1:19, v/v) there was prepared methyl (R) 4-[2-methoxycarbonyl-1-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-ethylcarbamoyl]-butyrate as a pale orange foam. MS(ES+) 659 (MH+), 681 (MNa+). MS(ES-) 658 (M-).
    • (j) By proceeding in a similar manner to Reference Example 4(a) but coupling [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid with (R) N-[2-methoxycarbonyl-1-(1,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-succinamate [Reference Example 13(b)] and subjecting the product to flash chromatography on silica eluting with a mixture of methanol and dichloromethane (1:19, v/v) there was prepared methyl (R) N-[2-methoxycarbonyl-1-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-succinamate as a light orange foam. MS(ES+) 667 (MNa+).
    • (k) By proceeding in a similar manner to Reference Example 4(a) but coupling ethyl (R/S) 3-(1,2,3,4-tetrahydro-quinolin-6-yl)butyrate [Reference Example 5(b)] with (1-boc-2-o-tolylamino-1H-benzimidazol-5-yl)-acetic acid (Reference Example 22) and subjecting the product to flash chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (3:7, v/v), there was prepared ethyl (R/S) 3-{1-[(2-o-tolylamino-3H-benzimidazol-5-yl)-acetyl]-1,2,3,4-tetrahydro-quinolin-6-yl}-butyric acid.
    • (l) By proceeding in a similar manner to Reference Example 4(a) but coupling [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid with (S) methyl 2-acetylamino-3-(1,2,3,4-tetrahydro-quinolin-6-yl)-propionate [Reference Example 19(b)] and subjecting the product to flash chromatography on silica eluting with a mixture of methanol and dichloromethane (1:19, v/v) there was prepared methyl (S) 2-acetylamino-3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl] acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-propionate as an off-white foam. MS(ES+) 573 (MH+), MS(ES-) 572 (M-).
    • (m) By proceeding in a similar manner to Reference Example 4(a) but coupling (2-o-tolylamino-benzoxazol-6-yl)-acetic acid with (S) Methyl 2-(N-boc-amino)-3-(1,2,3,4-tetrahydro-quinolin-6-yl)-propionate (Reference Example 19) and subjecting the product to flash chromatography on silica eluting with a mixture of ethyl acetate and dichloromethane (1:9, v/v) there was prepared (S) methyl 2-(N-boc-amino)-3-{1-[(2-o-tolylamino-benzoxazol-6-yl)-acetyl]-1,2,3,4-tetrahydro-quinolin-6-yl}-propionate as a colourless gum.
    • (n) By proceeding in a similar manner to Reference Example 4(a) but coupling 2-chlorobenzoic acid with methyl (S) 2-(N-boc-amino)-3-(1,2,3,4-tetrahydro-quinolin-6-yl)-propionate (Reference Example 19) and subjecting the product to flash chromatography on silica eluting with a mixture of ethyl acetate and dichloromethane (15:85, v/v) there was prepared methyl (S)-3-[1-(2-chloro-benzoyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-2-(N-boc-amino)-propionate as a colourless oil.
    • (o) By proceeding in a similar manner to Reference Example 4(a) but coupling (4-acetoxy-3-chloro-phenyl)-acetic acid with methyl (S) 2-(N-boc-amino)-3-(1,2,3,4-tetrahydro-quinolin-6-yl)-propionate (Reference Example 19) and subjecting the product to flash chromatography on silica eluting with a mixture of ethyl acetate and dichloromethane (15:85, v/v) there was prepared (S) methyl 3-{1-[(4-acetoxy-3-chloro-phenyl)-acetyl]-1,2,3,4-tetrahydro-quinolin-6-yl)-2-(N-boc-amino)-propionate as a colourless oil.
    • (p) By proceeding in a similar manner to Reference Example 4(a) but coupling 3-methoxy-4-(3-o-tolyl-ureido)-phenylacetic acid with ethyl (R/S) 3-(2,3-dihydro-1H-indol-5-yl)-heptanoate [Reference Example 24(a)] and subjecting the product to flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (11:9, v/v) there was prepared ethyl (R/S) 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-heptanoate as a foam.
    • (q) By proceeding in a similar manner to Reference Example 4(a) but coupling 4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenylacetic acid with ethyl (R/S) 3-(2,3-dihydro-1H-indol-5-yl)-heptanoate [Reference Example 24(a)] there was prepared ethyl (R/S) 3-[-({4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetyl)-2,3-dihydro-1H-indol-5-yl]-heptanoate as a white solid. MS (ES+) 606(MNa+).
    • (r) By proceeding in a similar manner to Reference Example 4(a) but coupling 3-methoxy-4-(3-o-tolyl-ureido)-phenylacetic acid with ethyl (R/S) 3-(2,3-dihydro-1H-indol-5-yl)-pentanoate [Reference Example 24(b)] and subjecting the product to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (99:1, v/v) there was prepared ethyl (R/S) 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-pentanoate as a glass.
    • (s) By proceeding in a similar manner to Reference Example 4(a) but coupling 4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenylacetic acid with ethyl (R/S) 3-(2,3-dihydro-1H-indol-5-yl)-pentanoate [Reference Example 24(b)] there was prepared ethyl (R/S) 3-[-({4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetyl)-2,3-dihydro-1H-indol-5-yl]-pentanoate as a white solid. MS (ES+) 578 (MNa+).
    • (t) By proceeding in a similar manner to Reference Example 4(a) but coupling 3-methoxy-4-(3-o-tolyl-ureido)-phenylacetic acid with ethyl (R/S) 3-(2,3-dihydro-1H-indol-5-yl)-3-phenyl-propionate [Reference Example 24(c)] and subjecting the product to flash chromatography on silica eluting with a mixture of pentane and ethyl acetate (1:1, v/v) there was prepared ethyl (R/S) 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-3-phenyl propionate as a foam.
    • (u) By proceeding in a similar manner to Reference Example 4(a) but coupling 4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenylacetic acid with ethyl (R/S) 3-(2,3-dihydro-1H-indol-5-yl)-3-phenyl-propionate [Reference Example 24(c)] there was prepared ethyl (R/S) 3-[-({4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetyl)-2,3-dihydro-1H-indol-5-yl]-3-phenyl-propionate as an off-white solid. MS (ES+) 626 (MNa+).
    REFERENCE EXAMPLE 5
    • (a) Ethyl (R/S) 3-(2,3-dihydro-1H-indol-5-yl)butyrate
      A solution of (R/S) ethyl 3-(1-boc-2,3-dihydro-1H-indol-5-yl)butyrate (3.1g, Reference Example 6) in dichloromethane (30ml), cooled in an ice bath, was treated with trifluoroacetic acid (30ml). After about 30 minutes the reaction mixture was evaporated and traces of trifluoroacetic acid were removed by chasing off with toluene (twice), to give the title compound as a dark viscous gum, which was used immediately without further purification.
    • (b) By proceeding in a similar manner as in reference Example 4(a) but using ethyl (R/S) 3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)butyrate (Reference Example 11) there was prepared ethyl (R/S) 3-(1,2,3,4-tetrahydro-quinolin-6-yl)butyrate.
    • (c) By proceeding in a similar manner as in reference Example 4(a) but using (R/S) 4-(1-boc-1,2,3,4-tetrahydro-quinotin-6-yl)-tetrahydro-pyran-2-one (Reference Example 16) and carrying out the reaction at room temperature there was prepared (R/S) 4-(1,2,3,4-tetrahydro-quinolin-6-yl)-tetrahydro-pyran-2-one as a brown solid.
    REFERENCE EXAMPLE 6 (R/S) Ethyl 3-(1-boc-2,3-dihydro-1H-indol-5-yl)butyrate
  • A mixture of ethyl 3-(1-boc-2,3-dihydro-1H-indol-5-yl)crotonate (11.4g, Reference Example 7) and ammonium formate (about 30g) in ethanol (about 200ml) was warmed in an oil-bath to 60°C. Palladium on charcoal (10%, about 1g) was added in one portion under a blanket of nitrogen - effervescence began almost immediately. The mixture was stirred at about 60°C for about one hour, then cooled to room temperature and filtered through Celite. The filtrate was evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water, then dried and then evaporated to give the title compound (11.1g) as a colourless, mobile oil.
    • REFERENCE EXAMPLE 7
    • (a) Ethyl 3-(1-boc-2.3-dihydro-1H-indol-5-yl)crotonate
      A mixture of 1-boc-5-bromoindoline (15.0g, Reference Example 8), ethyl crotonate (8.6g), palladium acetate (480mg), tris(o-tolyl)phosphine (1.6g) and triethylamine (10ml) in dimethylformamide (60ml) was stirred in a sealed vessel under an atmosphere of argon at about 100°C for about 4 hours. After cooling to room temperature the dark mass was poured onto hydrochloric acid (about 1L, 1M) and the product extracted into ethyl acetate. The combined extracts were washed with aqueous sodium bicarbonate solution, then with brine, then dried and then evaporated. The residual light yellow oil was subjected to flash chromatography on silica eluting initially with a mixture of ethyl acetate and petrol (5:95, v/v) to remove high running impurities, then eluting with a mixture of ethyl acetate and petrol (1:9, v/v) to give the title compound (11.4g) as a colourless, mobile oil.
    • (b) By proceeding in a similar manner to Reference Example 7(a) but using methyl acrylate and carrying out the reaction at 80°C there was prepared methyl 3-(1-boc-2,3-dihydro-1H-indol-5-yl)acrylate as a light yellow solid. MS(ES+) 629 (2MNa+).
    • (c) By proceeding in a similar manner to Reference Example 7(a) but using 1-boc-6-iodo-1,2,3,4-tetrahydroquinoline (Reference Example 12) there was prepared ethyl 3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)crotonate as a light yellow solid.
    • (d) By proceeding in a similar manner to Reference Example 7(a) but using 1-boc-6-iodo-1,2,3,4-tetrahydroquinoline (Reference Example 12) and methyl acrylate and carrying out the reaction at 80°C there was prepared methyl 3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)acrylate as a light yellow powder.
    REFERENCE EXAMPLE 8 1-boc-5-bromoindoline
  • 5-bromoindoline (10g) was added in one portion to molten Boc-anhydride (11.6g) at 30-40°C. Immediate effervescence was followed by the formation of a solid cake which was triturated with pentane to give the title compound (15g) as a white powder.
    • REFERENCE EXAMPLE 9
    • (a) Dimethyl 2-(2,3-dihydro-1H-indol-5-ylmethyl)-pentanedioate
      A mixture of dimethyl 3-(1-boc-2,3-dihydro-1H-indol-5-yl)-2-methoxycarbonyl-pentanedioate [530mg, Reference Example 10(a)] and concentrated hydrochloric acid (20ml) was stirred at reflux overnight then evaporated. The residual clear foam (370mg) was treated with methanol (20ml), then with concentrated sulphuric acid (10 drops). The resulting solution was stirred at reflux for 2 hours then evaporated. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer and extracts were washed with brine, then dried and then evaporated. The residue was subjected to flash chromatography or silica eluting with a mixture of ethyl acetate and petrol (1:1, v/v) to give the title compound (150mg) as a clear oil. MS(ES+) 278 (MH+).
    • (b) By proceeding in a similar manner to Reference Example 9(a) but using ethyl 3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)-2-ethoxycarbonyl-pentanedioate [Reference Example 10(b)] there was prepared dimethyl 3-(1,2,3,4-tetrahydro-quinolin-6-yl)-pentanedioate as a colourless oil. MS(ES+) 292 (MH+), 314 (MNa+).
    REFERENCE EXAMPLE 10
    • (a) Dimethyl 3-(1-boc-2,3-dihydro-1H-indol-5-yl)-2-methoxycarbonyl-pentanedioate
      A stirred solution of sodium (156mg) in methanol (15ml) was treated with dimethyl malonate (0.8ml) and after stirring for 15 minutes the mixture was then treated with a solution of methyl 3-(1-boc-2,3-dihydro-1H-indol-5-yl)acrylate [1.0g, reference Example 7(b)] in tetrahydrofuran (15ml). The mixture was stirred at reflux for 3 hours, then cooled to room temperature, then treated with water (2ml) and then evaporated. The residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with fresh ethyl acetate. The combined organic layer and extracts were washed with brine, then dried and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and petrol (15:85, v/v) to give the title compound (530mg) as a clear oil. MS(ES+) 458 (MNa+). MS(ES-) 434 (M-).
    • (b) By proceeding in a similar manner to Reference Example 10(a) but using methyl 3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)acrylate [Reference Example 7(d)] there was prepared ethyl 3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)-2-ethoxycarbonyl-pentanedioate. MS(ES+) 514 (MNa+). MS(ES-) 490 (M-).
    REFERENCE EXAMPLE 11
    • (a) Ethyl (R/S) 3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)butyrate
      A mixture of ethyl 3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)crotonate [9g, Reference Example 7(c)] and 5% palladium on charcoal (2.5g) in ethanol (250ml) was hydrogenated at room temperature and pressure overnight. The spent catalyst was removed by filtration through Celite and the filtrate was evaporated to give the title compound (9.1g) as a colourless oil.
    • (b) By proceeding in a similar manner to Reference Example 11(a) but using E and Z ethyl 3-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-hept-2-enoate [Reference Example 26(a)] and carrying out the hydrogenation at 2bar pressure of hydrogen gas for 4.5hours there was prepared ethyl (R/S) 3-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-heptanoate as a white solid.
    • (c) By proceeding in a similar manner to Reference Example 11(a) but using E and Z ethyl 3-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-pent-2-enoate [Reference Example 26(b)] and carrying out the hydrogenation at 2bar pressure of hydrogen gas for 100 minutes there was prepared ethyl (R/S) 3-(1-acetyl-2,3-dihvdro-1H-indol-5-yl)-pentanoate as a white solid.
    • (d) By proceeding in a similar manner to Reference Example 11(a) but using E and Z ethyl 3-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-cinnamate [Reference Example 26(c)] and carrying out the hydrogenation at 2bar pressure of hydrogen gas for 120 minutes there was ethyl (R/S) 3-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-3-phenyl-propionate as a white solid.
    REFERENCE EXAMPLE 12 1-Boc-6-iodo-1,2,3,4-tetrahydroquinoline
  • A solution of iodine monochloride (16.2g) in acetic acid (30ml) was added to a stirred solution of 1,2,3,4-tetrahydroquinoline (12.6ml) in acetic acid (125ml) at room temperature under nitrogen. After stirring at room temperature for a further hour the dark mixture was poured onto water (about 500ml) and the mixture was basified by the cautious addition of solid potassium carbonate. The aqueous layer was extracted with tert-butyl methyl ether, and this extract was washed successively with aqueous sodium thiosulphate solution, then with brine, then dried and then evaporated. The residual brown gum (22g) was treated with boc anhydride (44g) in tetrahydrofuran (250ml). The mixture was stirred at reflux overnight then evaporated and the residue was partitioned between ethyl acetate and dilute hydrochloric acid. The organic layer was washed with brine, then dried and then evaporated. Crystallisation of the residue from heptane gave the title compound (15g) as a light yellow powder.
    • REFERENCE EXAMPLE 13
    • (a) Methyl (R) 4-[1-(1,2,3,4-tetrahydro-quinolin-6-yl)-2-methoxycarbonyl-ethylcarbamoyl]-butyrate
      A stirred solution of methyl (R) 3-amino-3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)-propionate (1.7g, Reference Example 14) in tetrahydrofuran (50ml) was treated with glutaric anhydride. After stirring for 4 hours the mixture was evaporated to dryness the residue was dissolved in methanol (40ml) and treated with conc. sulphuric acid (20 drops). This solution was stirred at reflux for 3 hours and then allowed to stand at room temperature overnight. After the addition of solid sodium bicarbonate (10g) the mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The aqueous layer was extracted with fresh ethyl acetate. The combined organic layer and extracts were washed with brine, then dried and then evaporated. The residue was subjected to flash chromatography on silica eluting with ethyl acetate to give the title compound (1.6g) as a yellow oil. MS(ES+) 363 (MH+), 385 (MNa+) MS(ES-)361 (MH-).
    • (b) By proceeding in a similar manner to Reference Example 13(a) but using succinic anhydride there was prepared (R) N-[2-methoxycarbonyl-1-(1,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-succinamate as a colourless oil. MS(ES+) 371 (MNa+).
    REFERENCE EXAMPLE 14 (R) Methyl 3-amino-3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)-propionate
  • A solution of methyl 3-{R}-[benzyl-({S}-1-phenyl-ethyl)-amino]-3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)-propionate (6.5g, Reference Example 15) in ethanol (100ml) was treated with 20% palladium hydroxide on charcoal (1.0g), acetic acid (3.6ml) and water (10ml) and the mixture was hydrogenated at room temperature overnight. The spent catalyst was removed by filtration through Celite and the filtrate was evaporated to low bulk. The residue was taken up in ether and this solution was washed with aqueous sodium bicarbonate solution, and the layers separated. The aqueous layer was extracted twice with fresh ether and the combined ether extracts were washed with brine, then dried and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of methanol and dichloromethane (1:9, v/v) to give the title compound (1.7g) as a clear oil which slowly crystallised on standing. MS(ES+) 335(MH+), 357 (MNa+), 669 (2MH+)
    • REFERENCE EXAMPLE 15 Methyl 3-{R}-[benzyl-({S}-1-phenyl-ethyl)-amino]-3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)-propionate
  • A solution of (S)-N-benzyl-α-methylbenzylamine (2.6ml) in anhydrous tetrahydrofuran (50ml), cooled to -70°C and under nitrogen, was treated dropwise with a solution of butyllithium in hexanes (5ml, 2.5M) over about 5 minutes to give a red solution. After stirring at -70°C for a further 40 minutes the mixture was treated dropwise with a solution of methyl 3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)acrylate [2.0g, Reference Example 7(d)] in tetrahydrofuran (20ml) over about 10 minutes. Stirring was continued at low temperature for a further 20 minutes and then the reaction mixture was allowed to warm to room temperature. The mixture was partitioned between ether and water, the layers separated, and the organic layer washed with water then with brine, then dried and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and petrol (initially 1:9 and then 15:85, v/v) to give the title compound as a viscous, colourless oil, 1.5g.
    • REFERENCE EXAMPLE 16 (R/S) 4-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)-tetrahydro-pyran-2-one
  • A mixture of 1-boc-6-iodo-1,2,3,4-tetrahydroquinoline (2.0g, Reference Example 12), 5,6-dihydro-pyran-2-one (1.1g), tetrakis(triphenylphosphine)palladium (0) and triethylamine (2.2g) in dimethylformamide (5ml) was stirred at about 95°C in a sealed vessel under an atmosphere of nitrogen overnight. The reaction mixture was partitioned between ethyl acetate and dilute hydrochloric acid, the layers separated, and the organic layer washed with sodium bicarbonate solution, then dried, and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (2:3,v/v) to give the title compound as a brown oil, 1.2g.
    • REFERENCE EXAMPLE 17 Methyl (R) 3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)-3-[(5-methyl-isoxazole-3-carbonyl)-amino]-propionate
  • A solution of 5-methyl-isoxazole-3-carboxylic acid (65mg) in dimethylformamide (30ml) was treated successively with O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (190mg), diisopropylethylamine (1ml) and methyl (R) 3-amino-3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)-propionate (200mg, Reference Example 14). After standing at room temperature overnight the mixture was evaporated to low bulk and the residue partitioned between ethyl acetate and dilute hydrochloric acid. The layers were separated and the organic layer was washed with sodium carbonate solution, dried, and evaporated. The residue was purified by flash chromatography to give the title compound as an orange gum, 310mg.
    • REFERENCE EXAMPLE 18 Methyl (S) 2-amino-3-[1-(2,6-dichloro-benzoyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-propionate
  • A solution of methyl (S) 2-(N-boc-amino)-3-(1,2,3,4-tetrahydro-quinolin-6-yl)-propionate [500mg, Reference Example 19(a)] in tetrahydrofuran (20ml) was treated successively with triethylamine (360mg) and 2,6-dichlorobenzoyl chloride (380mg). The mixture was stirred at 40°C for 2 hours and then partitioned between ethyl acetate (100ml) and dilute hydrochloric acid (100ml). The organic phase was washed with sodium bicarbonate solution, then dried and that evaporated. The residue was dissolved in trifluoroacetic acid (2ml) and the clear solution was left at room temperature for 30 minutes then evaporated. The residue was partitioned between ethyl acetate and dilute hydrochloric acid. The organic phase was washed with sodium bicarbonate solution, then dried and then evaporated to give the title compound (200mg) as a colourless oil.
    • REFERENCE EXAMPLE 19
    • (a) (S) Methyl 2-(N-boc-amino)-3-(1,2,3,4-tetrahydro-quinolin-6-yl)-propionate
      A solution of methyl (S) 2-(N-boc-amino)-3-quinolin-6-yl-propionate [3.8g, Reference Example 20(a)] in ethanol (100ml) at 60°C was treated with ammonium formate (10g) and 10% palladium on charcoal (500mg). After stirring at 60°C further ammonium formate (about 5g) and palladium on charcoal (about 250mg) were added, and this was repeated at 30 minute intervals for a further 2 hours, at which time TLC analysis indicated the reaction was complete. After cooling to room temperature the mixture was filtered through Celite to remove spent catalyst, and the filtrate was evaporated. The residue was partitioned between ethyl acetate (200ml) and sodium bicarbonate solution (200ml). The organic phase was dried and evaporated to give the title compound (3.8g) as a colourless oil which slowly crystallised on standing.
    • (b) By proceeding in a similar manner to Reference Example 19(a) but using methyl (S) 2-(acetylamino)-3-quinolin-6-yl-propionate [Reference Example 20(b)] and carrying out the reaction at reflux temperature for 2 hours there was prepared methyl (S) 2-acetylamino-3-(1,2,3,4-tetrahydro-quinolin-6-yl)-propionate as a colourless oil. MS(ES+) 277 (MH+), 299 (MNa+).
    REFERENCE EXAMPLE 20
    • (a) Methyl (S) 2-(N-boc-amino)-3-quinolin-6-yl-propionate
      A mixture of methyl (S) 2-amino-3-quinolin-6-yl-propionate (3.0g, Reference Example 21) and boc-anhydride (3.2g) in tetrahydrofuran (30ml) was stirred at reflux for 30 minutes. The reaction mixture was evaporated and the residue was triturated with pentane to give the title compound (3.8g) as a white powder.
    • (b) By proceeding in a similar manner to Reference Example 20(a) but using acetic anhydride there was prepared methyl (S) 2-(acetyl-amino)-3-quinolin-6-yl-propionate as a colourless oil which crystallised slowly on standing. MS(ES+) 273 (MH+), MS(ES-) 271 (M-).
    REFERENCE EXAMPLE 21 Methyl (S) 2-amino-3-ctuinolin-6-yl-propionate
  • A solution of butyllithium in hexanes (13.4ml, 2.5M) was added dropwise to a stirred solution of (R) 2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (5.2g) in anhydrous tetrahydrofuran (80ml) at -78°C under an atmosphere of nitrogen. After stirring at -78°C for 10 minutes this solution was treated with a solution of 6-(chloromethyl)quinoline [5.0g, prepared according to the procedure described by Mahiou, Belaid; Gleicher, Gerald Jay. J. Org. Chem. (1990), 55(14), 4466-9] in tetrahydrofuran (20ml). The resultant dark orange mixture was stirred at -78°C for 2 hours. The cold reaction mixture was poured onto a mixture of ethyl acetate (200ml) and brine (200ml). The organic phase was dried and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and dichloromethane (1:1, v/v) to give a colourless oil (6g). This material was treated with hydrochloric acid (250ml, 0.25M) and the resulting solution was allowed to stand at room temperature for one hour then evaporated. The residue was treated with water (30ml) and the solution basified by addition of concentrated ammonia (50ml). This mixture was extracted three times with dichloromethane (100ml). The combined extracts were dried and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate to remove high running impurities and then with a mixture of methanol and ethyl acetate (1:1, v/v) to give the title compound (3.0g) as a colourless gum.
    • REFERENCE EXAMPLE 22 (1-Boc-2-o-tolylamino-1H-benzimidazol-5-yl)-acetic acid
  • Ethyl (R/S) (2-o-tolylamino-1H-benzimidazol-5-yl)-acetate (1.6g, Reference Example 23) was suspended in ethanol (30ml) and treated with sodium hydroxide solution (5ml, 1M). After stirring at 40°C for 2 hours the mixture was evaporated. The residue was partitioned between dilute acetic acid (50ml) and dichloromethane (50ml) and the resulting white precipitate (650mg) was dissolved in acetonitrile (30ml) and the solution was then treated with boc-anhydride (580mg) and dimethylaminopyridine (10mg). After standing at room temperature overnight the mixture was evaporated and the residue was partitioned between ethyl acetate and dilute acetic acid. The organic layer was dried and then evaporated. The residue was dissolved in methanol (2ml) and the solution was treated with ether. The resulting precipitate was collected by filtration to the title compound (500mg) as a white powder.
    • REFERENCE EXAMPLE 23 Ethyl (R/S) (2-o-tolylamino-1H-benzimidazol-5-yl)-acetate
  • A solution of ethyl (3,4-diaminophenyl)acetate (4.1g) in ethanol (50ml) and treated with o-tolylisothiocyanate (3.1g). After standing at room temperature overnight the clear solution was evaporated to give a yellow gum which was treated with ethanol (70ml). The resulting solution was treated with diisopropylcarbodiimide (5.3g), and the mixture stirred at 55°C for 4 hours then evaporated. The residue was subjected to by flash chromatography on silica eluting initially with ether and then with a mixture of methanol and ether (1:9, v/v), to give the title compound (4.1g) as a light yellow gum.
    • REFERENCE EXAMPLE 24
    • (a) Ethyl (R/S) 3-(2,3-dihydro-1H-indol-5-yl)-heptanoate
      A solution of R/S 3-(2,3-dihydro-1H-indol-5-yl)-heptanoic acid hydrochloride [4.13g, Reference Example 25(a)] in absolute ethanol (100mL) containing concentrated sulphuric acid (1.4mL) was stirred for 6 hours then allowed to stand overnight at room temperature. The mixture was concentrated to a low volume and the residue was partitioned between ethyl acetate (200mL) and saturated aqueous sodium bicarbonate (200mL). The organic phase was washed with saturated aqueous sodium bicarbonate (50mL). The aqueous phases were further extracted with ethyl acetate and the combined organic phases were dried over magnesium sulphate then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of pentane and ethyl acetate (2:1, v/v) to give the title compound (2.88g) as a pale yellow oil.
    • (b) By proceeding in a similar manner to Reference Example 24(a) but using R/S 3-(2,3-dihydro-1H-indol-5-yl)-pentanoic acid hydrochloride [Reference Example 25(b)] there was prepared ethyl (R/S) 3-(2.3-dihydro-1H-indol-5-yl)-pentanoate as a light yellow oil.
    • (c) By proceeding in a similar manner to Reference Example 24(a) but using R/S 3-(2,3-dihydro-1H-indol-5-yl)-3-phenyl-propionic acid hydrochloride [Reference Example 25(c)] there was prepared ethyl (R/S) 3-(2,3-dihydro-1H-indol-5-yl)-3-phenyl-propionate as a light orange oil.
    REFERENCE EXAMPLE 25
    • (a) (R/S) 3-(2,3-Dihydro-1H-indol-5-yl)-heptanoic acid hydrochloride
      A suspension of ethyl (R/S) 3-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-heptanoate [3.95g, Reference Example 11(b)] in aqueous hydrochloric acid (120mL, 6M) was heated at 85°C for 7 hours. After cooling to room temperature the mixture was evaporated. The residue was treated with toluene and the solvent evaporated under reduced pressure (repeated twice more). Final drying in a dessicator afforded the title compound (4.13g) as an orange-brown oil. LC-MS: RT=3.36 minutes; M(ES+) 248 (MH+).
    • (b) By proceeding in a similar manner to Reference Example 25(a) but using ethyl (R/S) 3-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-pentanoate [Reference Example 11(c)] there was prepared (R/S) 3-(2,3-dihydro-1H-indol-5-yl)-pentanoic acid hydrochloride as a brown oil.
    • (c) By proceeding in a similar manner to Reference Example 25(a) but using ethyl (R/S) 3-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-3-phenyl-propionate [Reference Example 11(d)] there was prepared R/S 3-(2,3-dihydro-1H-indol-5-yl)-3-phenyl-propionic acid hydrochloride as a brown solid.
    REFERENCE EXAMPLE 26
    • (a) E and Z Ethyl 3-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-hept-2-enoate
      Sodium hydride (1.09g, 60% dispersion in mineral oil) was suspended in tetrahydrofuran (150mL). The mixture was cooled in an ice-bath under a nitrogen atmosphere and triethyl phosphonoacetate (4.75mL) was added during 3 minutes. After 45 minutes a solution of 1-acetyl-5-pentanoyl-2,3-dihydro-1H-indole [5.33g, Reference Example 27(a)] in tetrahydrofuran (50mL) was added dropwise over 50 minutes. After stirring for 15 minutes the reaction mixture was allowed to warm to room temperature, then heated on a steam bath for 20 hours under a nitrogen atmosphere. In a separate flask, sodium hydride (1.09g, 60% dispersion in mineral oil) was suspended in tetrahydrofuran (150mL). The mixture was cooled in an ice-bath under a nitrogen atmosphere, triethyl phosphonoacetate (4.75mL) was added during 3 minutes and the mixture was stirred for 70 minutes. This mixture was added by canula to the main reaction mixture with ice-bath cooling. The reaction mixture was then refluxed for 43 hours, then cooled, then concentrated to half volume and then partitioned between ethyl acetate and 0.33M aqueous hydrochloric acid. The organic phase was separated and the aqueous phase re-extracted with ethyl acetate. The combined organics were dried over magnesium sulphate then evaporated to give an orange-brown oil which was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:1, v/v) to give the title compound (4.3g).
    • (b) By proceeding in a similar manner to Reference Example 26(a) but using 1-acetyl-5-propanoyl-2,3-dihydro-1H-indole (Reference Example 27(b)] there was prepared E and Z ethyl 3-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-pent-2-enoate as a cream solid.
    • (c) By proceeding in a similar manner to Reference Example 26(a) but using 1-acetyl-5-benzoyl-2,3-dihydro-1H-indole (Reference Example 27(c)] there was prepared E and Z ethyl 3-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-cinnamate as a yellow solid.
    REFERENCE EXAMPLE 27
    • (a) 1-acetyl-5-pentanoyl-2,3-dihydro-1H-indole
      Pentanoyl chloride (10.8g) was added dropwise to a mixture of anhydrous aluminium chloride (28.2g) and 1-acetyl-2,3-dihydro-1H-indole (10g) in 1,2-dichloroethane (100mL) with mechanical stirring. The mixture was stirred at reflux for 16 hours, then cooled, then poured into ice-water. The mixture was extracted with dichloromethane. The extracts were washed with 1M aqueous sodium hydroxide, then dried over magnesium sulphate, then evaporated to give the title compound (10.3g) as a dark gum.
    • (b) By proceeding in a similar manner to Reference Example 27(a) but using propionyl chloride and subjecting the product to flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (3:2, v/v) there was prepared 1-acetyl-5-propanoyl-2,3-dihydro-1H-indole as a cream-orange solid.
    • (c) By proceeding in a similar manner to Reference Example 27(a) but using benzoyl chloride and subjecting the product to flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (3:2, v/v) there was prepared 1-acetyl-5-benzoyl-2,3-dihydro-1H-indole as a cream solid.
    REFERENCE EXAMPLE 28 (R/S) 6-(2-Carboxy-1-methyl-ethyl)-3,4-dihydro-2H-quinoline-1-carboxylic acid 9H-fluoren-9-ylmethyl ester
  • A suspension of (R/S) 3-(1,2,3,4-tetrahydro-quinolin-6-yl)-butyric acid (2.6g) and sodium bicarbonate (2.2g) in acetone (40ml) and water (40ml) was treated with 2,5-dioxo-pyrrolidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (4.0g) and the resulting mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate evaporated to low bulk. The residue was treated with dilute hydrochloric acid and the resulting gummy precipitate was extracted into a mixture of tetrahydrofuran, ethyl acetate and dichloromethane. This solution was washed with brine, then dried and then evaporated to give the title compound (5.8g) as a light brown oil, which solidified on standing. MS (ES+) 464 (MNa+), MS(ES-) 440 (M-).
    • IN VITRO AND IN VIVO TEST PROCEDURES 1.Inhibitory effects of compounds on VLA4 dependent cell adhesion to Fibronectin and VCAM. 1.1 Metabolic labelling of RAMOS cells.
  • RAMOS cells (a pre-B cell line from ECACC, Porton Down, UK) are cultured in RPMI culture medium (Gibco, UK) supplemented with 5% foetal calf serum (FCS, Gibco, UK). Prior to assay the cells are suspended at a concentration of 0.5 X 106 cells/ml RPMI and labelled with 400µCi/100mls of [3H]-methionine (Amersham, UK) for 18 hours at 37°C.
    • 1.2 96 well plate preparation for adhesion assay.
  • Cytostar plates (Amersham, UK) were coated with 50µl/well of either 3µg/ml human soluble VCAM-1 (R&D Systems Ltd, UK) or 28.8µg/ml human tissue Fibronectin (Sigma, UK). In control non-specific binding wells 50µl phosphate buffered saline was added. The plates were then left to dry in an incubator at 25°C, overnight. The next day the plates were blocked with 200µl/well of Pucks buffer (Gibco, UK) supplemented with 1% BSA (Sigma, UK). The plates were left at room temperature in the dark for 2 hours. The blocking buffer was then disposed of and the plates dried by inverting the plate and gently tapping it on a paper tissue. 50µl/well of 3.6% dimethyl sulphoxide in Pucks buffer supplemented with 5mM manganese chloride (to activate the integrin receptor Sigma, UK) and 0.2% BSA (Sigma, UK), was added to the appropriate control test binding and non-specific binding assay wells in the plate. 50µl/well of the test compounds at the appropriate concentrations diluted in 3.6% dimethyl sulphoxide in Pucks buffer supplemented with 5mM manganese chloride and 0.2% BSA, was added to the test wells. Metabolically labelled cells were suspended at 4 x 106 cells/ml in Pucks buffer that was supplemented with manganese chloride and BSA as above. 50µl/well of cells in 3.6% dimethyl sulphoxide in Pucks buffer and supplements was added to all plate wells.
    The same procedure exists for plates coated with either VCAM-1 or fibronectin and data is determined for compound inhibition of cell binding to both substrates.
    • 1.3 Performance of assay and data analysis.
  • The plates containing cells in control or compound test wells are incubated in the dark at room temperature for 1 hour.
  • The plates are then counted on a Wallac Microbeta scintillation counter (Wallac, UK) and the captured data processed in Microsoft Excel (Microsoft, US). The data was expressed as an IC50, namely the concentration of inhibitor at which 50% of control binding occurs. The percentage binding is determined from the equation: { C TB - C NS - C I - C NS / C TB - C NS } × 100 = %  binding
    Figure imgb0287
    where CTB are the counts bound to fibronectin (or VCAM-1) coated wells without inhibitor present, CNS are the counts present in wells without substrate, and CI are the counts present in wells containing a cell adhesion inhibitor.
  • Compound data of this invention is expressed for IC50s for inhibition of cell adhesion to both fibronectin and VCAM-1. Particular compounds of the invention inhibit cell adhesion to fibronectin and VCAM-1 with IC50s in the range 100 micromolar to 0.1 nanomolar. Preferred compounds of the invention inhibit cell adhesion to fibronectin and VCAM-1 with IC50s in the range 10 nanomolar to 0.1 nanomolar.
    • 2. Inhibition of antigen-induced airway inflammation in the mouse and rat. 2.1 Sensitization of the animals.
  • Rats (Brown Norway, Harland Olac, UK) are sensitized on days 0, 12 and 21 with ovalbumin (100 µg, intraperitoneally [i.p], Sigma, UK) administered with aluminium hydroxide adjuvant (100mg, i.p., Sigma, UK) in saline (1ml, i.p.).
  • In addition mice (C57) are sensitized on days 0 and 12 with ovalbumin (10µg, i.p.) administered with aluminium hydroxide adjuvant (20mg, i.p.) in saline (0.2ml, i.p.).
    • 2.2 Antigen challenge.
  • Rats are challenged on any one day between days 28-38, while mice are challenged on any one day between days 20-30.
  • The animals are challenged by exposure for 30 minutes (rats) or 1 hour (mice) to an aerosol of ovalbumin (10g /1) generated by an ultrasonic nebulizer (deVilbiss Ultraneb, US) and passed into an exposure chamber.
    • 2.3 Treatment protocols.
  • Animals are treated, as required before or after antigen challenge. The aqueous-soluble compounds of this invention can be prepared in water (for oral, p.o. dosing) or saline (for intratracheal, i.t. dosing). Non-soluble compounds are prepared as suspensions by grinding and sonicating the solid in 0.5 % methyl cellulose / 0.2 % polysorbate 80 in water (for p.o. dosing, both Merck UK Ltd., UK or saline (for i.t. dosing). Dose volumes are: for rats 1ml /kg, p.o. or 0.5mg / kg, i.t.; for mice 10ml / kg, p.o. or 1ml / kg, i.t.
    • 2.4 Assessment of airway inflammation.
  • The cell accumulation in the lung is assessed 24 hours after challenge (rats) or 48-72 hours after challenge (mice). The animals are euthanized with sodium pentobarbitone (200mg/kg, i.p., Pasteur Merieux, France) and the trachea is immediately cannulated. Cells are recovered from the airway lumen by bronchoalveolar lavage (BAL) and from the lung tissue by enzymatic (collagenase, Sigma, UK) disaggregation as follows.
  • BAL is performed by flushing the airways with 2 aliquots (each 10 ml/kg) RPMI 1640 medium (Gibco, UK) containing 10 % fetal calf serum (FCS, Serotec Ltd., UK). The recovered BAL aliquots are pooled and cell counts made as described below.
  • Immediately after BAL, the lung vasculature is flushed with RPMI 1640 / FCS to remove the blood pool of cells. The lung lobes are removed and cut into 0.5 mm pieces. Samples (rats: 400mg; mice: 150mg) of homogenous lung tissue are incubated in RPMI 1640 / FCS with collagenase (20 U/ml for 2 hours, then 60 U/ml for 1 hour, 37°C) to disaggregate cells from the tissue. Recovered cells are washed in RPMI 1640 / FCS.
  • Counts of total leukocytes recovered from the airway lumen and the lung tissue are made with an automated cell counter (Cobas Argos, US). Differential counts of eosinophils, neutrophils and mononuclear cells are made by light microscopy of cytocentrifuge preparations stained with Wright-Giemza stain (Sigma, UK). T cells are counted by flow cytometry (EPICS XL, Coulter Electronics, US) using fluophore-labelled antibodies against CD2 (a pan-T cell marker used to quantify total T cells), CD4, CD8 and CD25 (a marker of activated T cells). All antibodies were supplied by Serotec Ltd., UK).
    • 2.5 Data analysis.
  • The cell data was expressed as mean cell numbers in unchallenged, challenged and vehicle treated, and challenged and compound treated groups, including the standard error of the means. Statistical analysis of the difference among treatment groups was evaluated using one-way analysis of variance via the Mann-Whitney test. Where p < 0.05 no statistical significance existed.

Claims (94)

  1. A compound of general formula (I):-
    Figure imgb0288
     wherein:-
    R1 represents:
    (i) R3-Z3-;
    (ii) R3-L2-R4-Z3-;
    (iii) R3-L3-Ar1-L4-Z3-; or
    (iv) R3-L3-Ar1-L2-R4-Z3-;
    R2 represents hydrogen, halogen, C1-4alkyl or C1-4alkoxy;
    R3 represents alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocycloalkyl or heterocycloalkylalkyl; R4 represents an alkylene chain, an alkenylene chain, or an alkynylene chain;
    R5 represents hydrogen or C1-4alkyl;
    R6 represents hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl or heteroarylalkyl;
    R7 and R7a are each independently hydrogen or C1-4alkyl;
    R8 represents hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
    R9 represents alkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, or alkyl substituted by aryl, an acidic functional group, cycloalkyl, heteroaryl, heterocycloalkyl, -S(O)mR3, -C(=O)-NY4Y5 or -NY4Y5;
    R10 represents hydrogen, R3 or alkyl substituted with alkoxy, cycloalkyl, hydroxy, mercapto, alkylthio or -NY4Y5;
    R11 and R13 are each independently selected from hydrogen or a group consisting amino acid side chains, an acidic functional group, R3, -C(=O)-R3, or -C(=O)-NY4Y5, or alkyl substituted by an acidic functional group or by R3, -NY4Y5, -NH-C(=O)-R3, -C(=O)-R4-NH2, -C(=O)-Ar1-NH2, -C(=O)-R4-CO2H, or -C(=O)-NY4Y5;
    or R10 and R11 or R10 and R12 together with the atoms to which they attached form a 3- to 6-membered heterocycloalkyl ring;
    R12 represents C1-6alkylene, optionally substituted by R3;
    R14 represents alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
    A1 represents a straight chain C1-2alkylene linkage optionally substituted by one or more groups chosen from alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, imino, oxo, thioxo, or alkyl substituted by -ZR6, -NY1Y2, -CO2R6 or -C(=O)-NY1Y2;
    Ar1 represents arylene or heteroaryldiyl;
    L1 represents:
    (i) a direct bond;
    (ii) an alkenylene, alkylene, alkynylene, cycloalkenylene, cycloalkylene, heteroaryldiyl, heterocycloalkylene or arylene linkage each optionally substituted by (a) an acidic functional group, cyano, oxo, -S(O)mR9, R3, -C(=O)-R3, -C(=O)-OR3, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9, -NY4Y5 or -[C(=O)-N(R10)-C(R5)(R11)]p-C(=O)-NY4Y5, or by (b) alkyl substituted by an acidic functional group, or by S(O)mR9, -C(=O)-NY4Y5 or -NY4Y5;
    (iii) a -[C(=O)-N(R10)-C(R5)(R11)]p- linkage;
    (iv) a -Z2-R12- linkage;
    (v) a -C(=O)-CH2-C(=O)- linkage;
    (vi) a -R12-Z2-R12- linkage;
    (vii) a -C(R4)(R13)-[C(=O)-N(R10)-C(R5)(R11)]p- linkage; or
    (viii) a -L5-L6-L7- linkage;
    L2 represents a -NR5-C(=Z)-NR5-, -C(=Z)-NR5-, -C(=O)-, -C(=Z)-O-, -NR5-C(=Z)-, -Z-, -S(O)m-, -NR5-, -SO2-NR5-, -NR5-SO2-, -NR5-C(=O)-O-, -O-C(=O)-, or -O-C(=O)-NR5-linkage;
    L3 represents a heteroaryldiyl, -NR5-C(=Z)-NR5-, -C(=Z)-NR5-, -C(=Z)-O-, -NR5-C(=Z)-, -Z-, -S(O)m-, -NR5-, -SO2-NR5-, -NR5-SO2-, -NR5-C(=O)-O-, -O-C(=O)-, or -O-C(=O)-NR5-linkage;
    L4 represents a direct bond, an alkylene, alkenylene or alkynylene chain;
    L5 and L7 each independently represent a direct bond or an alkylene chain;
    L6 represents a cycloalkylene or heterocycloalkylene linkage;
    Y1 and Y2 are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group -NY1Y2 may form a cyclic amine;
    Y4 and Y5 are independently hydrogen, alkenyl, alkyl, alkynyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, heterocycloalkyl, or alkyl substituted by alkoxy, aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl, hydroxy, oxo, -NY1Y2, or one or more -CO2R8 or -C(=O)-NY1Y2 groups; or the group -NY4Y5 may form a 5- to 7-membered cyclic amine which (i) may be optionally substituted with one or more substituents selected from alkoxy, carboxamido, carboxy, hydroxy, oxo (or a 5-, 6- or 7-membered cyclic acetal derivative thereof), R10; (ii) may also contain a further heteroatom selected from O, S, SO2, or NY6; and (iii) may also be fused to additional aryl, heteroaryl, heterocycloalkyl or cycloalkyl rings to form a bicyclic or tricyclic ring system;
    Y6 represents hydrogen, alkyl, aryl, arylalkyl, -C(=O)-R14, -C(=O)-OR14 or -SO2R14;
    Z is an oxygen or sulphur atom;
    Z1 is C(R7)(R7a), C(=O) or CH(OH);
    Z2 is O, S(O)n, NR5, SONR5, C(=O)NR5 or C(=O);
    Z3 is C(=O);
    m is an integer 1 or 2;
    n is zero or an integer 1 or 2;
    p is zero or an integer 1 to 4; and
    Y is carboxy; and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates of such compounds and their N-oxides and ester prodrugs, but excluding compounds where an oxygen, nitrogen or sulphur atom is attached directly to a carbon carbon multiple bond of an alkenylene, alkynylene or cycloalkenylene residue, and excluding N-acetylindoline-5-glycine;
    wherein,
    references to "alkyl" groups include, unless otherwise indicated, alkyl groups substituted by alkoxy or by one or more halogen atoms;
    "aryl" as a group or part of a group denotes: (i) a monocyclic or multicyclic aromatic carbocyclic moiety of 6 to 14 carbon atoms, or (ii) a partially saturated multicyclic aromatic carbocyclic moiety in which an aryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure and, unless otherwise indicated, include aryl groups substituted by one or more aryl group substituents which may be the same or different;
    "arylene" groups mean bivalent radicals derived from an aryl group;
    "cycloalkyl" means a saturated monocyclic or bicyclic ring system of 3 to 10 carbon atoms optionally substituted by oxo;
    "heteroaryl" as a group or part of a group denotes: (i) an aromatic monocyclic or multicyclic organic moiety of 5 to 10 ring members in which one or more of the ring members is/are element(s) other than carbon; or (ii) a partially saturated multicyclic heterocarbocyclic moiety in which a heteroaryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure, and includes heteroaryl groups substituted by one or more aryl group substituents;
    "heteroaryldiyl" means a bivalent radical derived from an aromatic monocyclic or multicyclic organic moiety of 5 to 10 ring members in which one or more of the ring members is/are element(s) other than carbon, and includes heteroaryldiyl groups optionally substituted by one or more aryl group substituents;
    "azaheteroaryldiyl" means an optionally substituted bivalent radical derived from a heteroaryl group;
    "heterocycloalkyl" means: (i) a cycloalkyl group of 3 to 7 ring members which contains one or more heteroatoms selected from O, S or NY3 and which may optionally be substituted by oxo; or (ii) an optionally substituted partially saturated multicyclic heterocarbocyclic moiety in which an aryl (or heteroaryl ring) and a heterocycloalkyl group are fused together to form a cyclic structure;
    wherein "aryl group substituent" includes acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulphinyl, alkylsulphonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulphinyl, arylsulphonyl, arylthio, carboxy, cyano, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, hydroxy, nitro, trifluoromethyl, Y1Y2N-, Y1Y2NCO-, Y1Y2NSO2-, Y1Y2N-C2-6alkylene-Z4- {where Z4 is O, NR6 or S(O)n}, alkylC(=O)-Y1N-, alkylSO2-Y1N- or alkyl optionally substituted with aryl, heteroaryl, hydroxy, or Y1Y2N-;
    and wherein said acidic functional group is selected from the group consisting of carboxyl, hydroxy, mercapto and imidazole.
  2. A compound according to claim 1 in which R1 represents a group R3-Z3- in which Z3 is C(=O) and R3 is aryl, heteroaryl or arylalkyl.
  3. A compound according to claim 2 in which R3 is phenyl or phenyl substituted by one or two of aryloxy, cyano, halo, C1-4alkoxy, C1-4alkyl, nitro or CF3.
  4. A compound according to claim 2 in which R3 is isoquinolinyl, isoxazolyl, pyrazolopyrimidinyl, pyridyl, pyrimidinyl, quinolinyl, thiazolyl and triazolyl, each optionally substituted by one or two of alkylcarbonyl, aryl, cyano, halo, C1-4alkoxy, C1-4alkyl, C1-4alkylsulphonyl, C1-4alkylthio, nitro or CF3.
  5. A compound according to claim 2 in which R3 is benzyl optionally substituted in the phenyl ring by one or two of halo, hydroxy or methoxy.
  6. A compound according to claim 2 in which R3 is 2-chlorophenyl, 5-chloro-2-cyanophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 4-nuoro-2-trinuoromethyl, 2-methyl-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2-nitrophenyl, 3-nitrophenyl or 2-phenoxyphenyl.
  7. A compound according to claim 1 in which R1 represents a group R3-L3-Ar1-L4-Z3- in which Z3 is C(=O), L4 is a straight or branched C1-6alkylene chain, Ar1 is optionally substituted phenylene or heteroaryldiyl, L3 is an -NH-C(=O)-NH- linkage and R3 is aryl or heteroaryl.
  8. A compound according to claim 7 in which L4 is methylene, Ar1 is optionally substituted p-phenylene and R3 is optionally substituted phenyl.
  9. A compound according to claim 8 in which Ar1 is p-phenylene or p-phenylene substituted in the 3-position by halo, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, C1-4alkylsulphinyl or C1-4alkylsulphonyl and R3 is phenyl substituted in the 2-position by C1-4alkyl.
  10. A compound according to claim 1 in which R1 represents a group R3-L3-Ar1-L4-Z3- in which Z3 is C(=O), L4 is a straight or branched C1-6alkylene chain, Ar1 is an optionally substituted 8 to 10 membered bicyclic system
    Figure imgb0289
     in which ring
    Figure imgb0290
     isa 5 or 6 membered heterocycle ring, ring
    Figure imgb0291
     is a 5 or 6 membered heterocycle or a benzene ring and the two rings are joined together by a carbon-carbon linkage or a carbon-nitrogen linkage, L3 represents NH and R3 is aryl.
  11. A compound according to claim 10 in which L4 is methylene and Ar1 is optionally substituted benzoxazolyl or optionally substituted benzimidazolyl.
  12. A compound according to claim 11 in which Ar1 is benzoxazolyl or benzimidazolyl each optionally substituted by one or more groups selected from C1-4alkyl, C1-4alkoxy, amino, halogen, hydroxy, C1-4alkylthio, C1-4alkylsulphinyl, C1-4alkylsulphonyl, nitro or trifluoromethyl, and R3 is phenyl substituted in the 2-position by C1-4alkyl, C1-4alkoxy, halo or diC1-4alkylamino.
  13. A compound according to claim 1 in which R1 represents a group R3-L3-Ar1-L4-Z3- in which Z3 is C(=O), L4 is a straight or branched C1-6alkylene chain, Ar1 is optionally substituted phenylene or heteroaryldiyl, L3 is -C(=O)-NH- and R3 is heterocycloalkyl.
  14. A compound according to claim 13 in which L4 is methylene and Ar1 is optionally substituted p-phenylene.
  15. A compound according to claim 14 in which Ar1 is p-phenylene or p-phenylene substituted in the 3-position by halo, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, C1-4alkylsulphinyl or C1-4alkylsulphonyl and R3 is indolinyl.
  16. A compound according to any preceding claim in which R2 is hydrogen.
  17. A compound according to any preceding claim in which A1 is an unsubstituted straight chain C1-2alkylene linkage.
  18. A compound according to claim 17 in which A1 is methylene.
  19. A compound according to claim 17 in which A1 is ethylene.
  20. A compound according to any preceding claim in which Z1 is CH2, CHOH or C(=O).
  21. A compound according to claim 20 in which Z1 is CH2.
  22. A compound according to any preceding claim in which L1 is an optionally substituted alkylene linkage.
  23. A compound according to claim 22 in which L1 is ethylene or propylene, each optionally substituted by C1-4alkyl, aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9, -NY4Y5 and -[C(=O)-N(R10)-C(R5)(R11)]p-C(=O)-NY4Y5 or alkyl substituted by carboxy, -ZH, -ZR3, -C(=O)-NY4Y5 or -NY4Y5 (wherein R3, R5, R8, R9, R10, R11, Y4, Y5, Z and p are as defined in claim 1).
  24. A compound according to claim 22 in which L1 is a group
    Figure imgb0292
     where R5 is hydrogen or C1-4alkyl and R15 is hydrogen or C1-4alkyl, or where R5 is hydrogen and R15 is aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9, -NY4Y5, -[C(=O)-N(R10)-C(R5)(R11)]p-C(=O)-NY4Y5, or alkyl substituted by carboxy or by -ZH, -ZR3, -C(=O)-NY4Y5 or -NY4Y5 (wherein R3, R5, R8, R9, R10, R11, Y4, Y5, Z and p are as defined in claim 1).
  25. A compound according to claim 24 in which L1 is a group
    Figure imgb0293
     where R15 represents hydrogen, C1-4alkyl, aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9 or -NY4Y5, or alkyl substituted by carboxy, -OH, -OR3 or -C(=O)-NY4Y5 (wherein R3, R8, R9, Y4 and Y5 are as defined in claim 1).
  26. A compound according to claim 24 in which L1 is a group
    Figure imgb0294
     where R15 represents hydrogen, C1-4alkyl, aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9 or -NY4Y5, or alkyl substituted by carboxy, -OH, -OR3 or -C(=O)-NY4Y5 (wherein R3, R8, R9, Y4 and Y5 are as defined in claim 1).
  27. A compound, according to claim 22 in which L1 is a group
    Figure imgb0295
     where R5 is hydrogen or C1-4alkyl and R15a represents C1-4alkyl, or where R5 is hydrogen and R15a represents aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9, -NY4Y5, -[C(=O)-N(R10)-C(R5)(R11)]p-C(=O)-NY4Y5, or alkyl substituted by carboxy or by -ZH, -ZR3, -C(=O)-NY4Y5 or -NY4Y5 (wherein R3, R5, R8, R9, R10, R11, Y4, Y5, Z and p are as defined in claim1).
  28. A compound according to claim 27 in which L1 is a group
    Figure imgb0296
     where R15a represents -N(R8)-C(=O)-R9 or -N(R8)-SO2-R9 (wherein R8 and R9 are as defined in claim 1).
  29. A compound according to claim 27 in which L1 is a group
    Figure imgb0297
     where R15a represents -N(R8)-C(=O)-R9 or -N(R8)-SO2-R9 (wherein R8 and R9 are as defined in claim 1).
  30. Use of a compound according to claim 1, or a corresponding N-oxide, or an ester prodrug thereof; or a pharmaceutically acceptable salt or solvate of such a compound or its N-oxide or an ester prodrug thereof in the manufacture of a medicament for the treatment of conditions which can be ameliorated by the administration of an inhibitor of α4β1 mediated cell adhesion.
  31. A compound according to claim 1 having the formula (Ia):-
    Figure imgb0298
     in which R2, R3, A1, Ar1, L1, L4, Y and Z1 are as defined in any relevant preceding claim, and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates of such compounds and their N-oxides and ester prodrugs.
  32. A compound according to claim 1 having the formula (Ib):-
    Figure imgb0299
     in which R2, R3, A1, L2, Y and Z1 are as defined in any relevant preceding claim, X is NR5 or O, Z4 represents a direct bond, NR5, O or S(O)n (where R5 and n are as defined in any relevant preceding claim), and R is hydrogen or an aryl group substituent, and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates of such compounds and their N-oxides and ester prodrugs.
  33. A compound according to claim 1 having the formula(Ic):-
    Figure imgb0300
     in which Ar1, L4, A1, R2, L1, Y and Z1 are as defined in any relevant preceding claim, and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates of such compounds and their N-oxides and ester prodrugs.
  34. A compound according to claim 1 having the formula(Id):-
    Figure imgb0301
     in which R3, A1, R2, L1, Y and Z1 are as defined in any relevant preceding claim, and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates of such compounds and their N-oxides and ester prodrugs.
  35. A compound according to claim 31 in which R3 is phenyl substituted in the 2-position by C1-4alkyl.
  36. A compound according to any one of claims 31, 33 and 35 in which Ar1 is p-phenylene or p-phenylene substituted in the 3-position by halo, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, C1-4alkylsulphinyl or C1-4alkylsulphonyl.
  37. A compound according to claim 32 in which R3 is phenyl substituted in the 2-position by C1-4alkyl, C1-4alkoxy, halo or diC1-4alkylamino.
  38. A compound according to claim 32 or claim 37 in which Z4 represents NH.
  39. A compound according to any one of claims 32, 37 and 38 in which R represents hydrogen, halo, C1-4alkyl or C1-4alkoxy.
  40. A compound according to any one of claims 31, 32, 33 and 35 to 39 in which L4 is a straight or branched C1-4alkylene chain.
  41. A compound according to claim 40 in which L4 is methylene.
  42. A compound according to claim 34 in which R3 is phenyl or phenyl substituted by one or two of aryloxy, cyano, halo, C1-4alkoxy, C1-4alkyl, nitro or CF3.
  43. A compound according to claim 34 in which R3 is benzyl optionally substituted in the phenyl ring by one or two of halo, hydroxy or methoxy.
  44. A compound according to claim 34 in which R3 is 2-chlorophenyl, 5-chloro-2-cyanophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 4-fluoro-2-trifluoromethyl, 2-methyl-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2-nitrophenyl, 3-nitrophenyl or 2-phenoxyphenyl.
  45. A compound according to any one of claims 31 to 44 in which A1 is an unsubstituted straight chain C1-2alkylene linkage.
  46. A compound according to claim 45 in which A1 is methylene.
  47. A compound according to claim 45 in which A1 is ethylene.
  48. A compound according to any one of claims 31 to 47 in which Z1 is CH2.
  49. A compound according to any one of claims 31 to 48 in which R2 is hydrogen.
  50. A compound according to any one of claims 31 to 49 in which L1 is an optionally substituted alkylene linkage.
  51. A compound according to claim 50 in which L1 is ethylene or propylene, each optionally substituted by C1-4alkyl, aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9, -NY4Y5 and -[C(=O)-N(R10)-C(R5)(R11)]p-C(=O)-NY4Y5 or alkyl substituted by carboxy, -ZH, -ZR3, -C(=O)-NY4Y5 or -NY4Y5 (wherein R3, R5, R8, R9, R10, R11, Y4, Y5, Z and p are as defined in claim 1).
  52. A compound according to claim 50 in which L1 is a group
    Figure imgb0302
     where R5 is hydrogen or C1-4alkyl and R15 is hydrogen or C1-4alkyl, or where R5 is hydrogen and R15 is aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9, -NY4Y5, -[C(=O)-N(R10)-C(R5)(R11)]p-C(=O)-NY4Y5, or alkyl substituted by carboxy or an acid bioisostere, or by -ZH, -ZR3, -C(=O)-NY4Y5 or -NY4Y5 (wherein R3, R5, R8, R9, R10, R11, Y4, Y5, Z and p are as defined in claim 1).
  53. A compound according to claim 52 in which L1 is a group
    Figure imgb0303
     where R15 represents hydrogen, C1-4alkyl, aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9 or -NY4Y5, or alkyl substituted by carboxy, -OH, -OR3 or -C(=O)-NY4Y5 (wherein R3, R8, R9, Y4 and Y5 are as defined in claim 1).
  54. A compound according to claim 52 in which L1 is a group
    Figure imgb0304
     where R15 represents hydrogen, C1-4alkyl, aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9 or -NY4Y5, or alkyl substituted by carboxy, -OH, -OR3 or -C(=O)-NY4Y5 (wherein R3, R8, R9, Y4 and Y5 are as defined in claim 1).
  55. A compound according to claim 50 in which L1 is a group
    Figure imgb0305
     where R5 is hydrogen or C1-4alkyl and R15a represents C1-4alkyl, or where R5 is hydrogen and R15a represents aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9, -NY4Y5, -[C(=O)-N(R10)-C(R5)(R11)]p-C(=O)-NY4Y5, or alkyl substituted by carboxy or by -ZH, -ZR3, -C(=O)-NY4Y5 or -NY4Y5 (wherein R3, R5, R8, R9, R10, R11, Y4, Y5, Z and p are as defined in claim1).
  56. A compound according to claim 55 in which L1 is a group
    Figure imgb0306
     where R15a represents -N(R8)-C(=O)-R9 or -N(R8)-SO2-R9 (wherein R8 and R9 are as defined in claim 1).
  57. A compound according to claim 55 in which L1 is a group
    Figure imgb0307
     where R15a represents -N(R8)-C(=O)-R9 or -N(R8)-SO2-R9 (wherein R8 and R9 are as defined in claim 1).
  58. Use of a compound according to claim 1, or a corresponding N-oxide, or an ester prodrug thereof; or a pharmaceutically acceptable salt or solvate of such a compound or its N-oxide or an ester prodrug thereof in the manufacture of a medicament for the treatment of asthma.
  59. A compound of formula (Ia) according to claim 31 in which R2 is hydrogen, R3 is a 2-substituted phenyl, A1 is methylene or ethylene, Ar1 is optionally substituted m- or p-phenylene or optionally substituted p-pyridinediyl, L1 is a
    Figure imgb0308
     [where R15 represents hydrogen, C1-4alkyl, aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9 or -NY4Y5, or alkyl substituted by carboxy, -OH, -OR3, -C(=O)-NY4Y5], L4 represents a straight or branched C1-6alkylene chain, and Z1 represents CH2; and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates of such compounds and their N-oxides and ester prodrugs.
  60. A compound of formula (Ia) according to claim 31 in which R2 is hydrogen, R3 is a 2-substituted phenyl, A1 is methylene or ethylene, Ar1 is optionally substituted m- or p-phenylene or optionally substituted p-pyridinediyl, L1 is a
    Figure imgb0309
     group [where R15a represents -N(R8)-C(=O)-R9, or -N(R8)-SO2-R9], L4 represents a straight or branched C1-6alkylene chain, and Z1 represents CH2; and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates of such compounds and their N-oxides and ester prodrugs.
  61. A compound of formula (Ib) according to claim 32 in which R is hydrogen, chloro, methyl, ethyl or methoxy, R2 is hydrogen, R3 is aryl, A1 is methylene or ethylene, L1 is a
    Figure imgb0310
     group [where R15 represents hydrogen, C1-4alkyl, aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9 or -NY4Y5, or alkyl substituted by carboxy, -OH, -ZR3, -C(=O)-NY4Y5 or -NY4Y5], L4 is a straight or branched C1-4alkylene chain, X is O, Z1 is CH2, Z4 is NH, and the group
    Figure imgb0311
     is attached at the ring 6 position; and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates of such compounds and their N-oxides and ester prodrugs.
  62. A compound of formula (Ib) according to claim 32 in which R is hydrogen, chloro, methyl, ethyl or methoxy, R2 is hydrogen, R3 is optionally substituted aryl, A1 is methylene or ethylene, L1 is a
    Figure imgb0312
     group [where R15a represents -N(R8)-C(=O)-R9 or -N(R8)-SO2-R9], L4 is a straight or branched C1-4alkylene chain, X is O, Z1 is CH2, Z4 is NH, and the group
    Figure imgb0313
     is attached at the ring 6 position; and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates of such compounds and their N-oxides and ester prodrugs.
  63. A compound of formula (Ib) according to claim 32 in which R2 is hydrogen, R3 is optionally substituted aryl, A1 is methylene or ethylene, L1 is a
    Figure imgb0314
     group [where R15 represents hydrogen, C1-4alkyl, aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9 or -NY4Y5, or alkyl substituted by carboxy, -OH, -OR3, -C(=O)-NY4Y5 or -NY4Y5], L4 is a straight or branched C1-4alkylene chain, X is NR5, Z1 is CH2, Z4 is NH, and the group
    Figure imgb0315
     is attached at the ring 5 or 6 position; and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates of such compounds and their N-oxides and ester prodrugs.
  64. A compound of formula (Ib) according to claim 32 in which R2 is hydrogen, R3 is aryl, A1 is methylene or ethylene, L1 is a
    Figure imgb0316
     group [where R15a represents -N(R8)-C(=O)-R9 or -N(R8)-SO2-R9], L4 is a straight or branched C1-4alkylene chain, X is NR5, Z1 is CH2, Z4 is NH, and the group
    Figure imgb0317
     is attached at the ring 5 or 6 position; and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates of such compounds and their N-oxides and ester prodrugs.
  65. A compound of formula (Ic) according to claim 33 in which R2 is hydrogen, A1 is methylene or ethylene, Ar1 is optionally substituted m- or p-phenylene or optionally substituted p-pyridinediyl, L1 is a
    Figure imgb0318
     group [where R15 represents hydrogen, methyl, aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9 or -NY4Y5, or alkyl substituted by carboxy, -OH, -OR3 or -C(=O)-NY4Y5], L4 is a straight or branched C1-4alkylene chain and Z1 is CH2; and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates of such compounds and their N-oxides and ester prodrugs.
  66. A compound of formula (Ic) according to claim 33 in which R2 is hydrogen, A1 is methylene or ethylene, Ar1 is optionally substituted m- or p-phenylene or optionally substituted p-pyridinediyl, L1 is a
    Figure imgb0319
     group [where R15a represents -N(R8)-C(=O)-R9 or -N(R8)-SO2-R9], L4 is a straight or branched C1-4alkylene chain and Z1 is CH2; and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  67. A compound of formula (Id) according to claim 34 in which R2 is hydrogen, R3 is optionally substituted phenyl, heteroaryl or optionally substituted benzyl, A1 is methylene or ethylene, L1 is a
    Figure imgb0320
     [where R15 represents hydrogen, methyl, aryl, heteroaryl, -N(R8)-C(=O)-R9, -N(R8)-C(=O)-OR9, -N(R8)-SO2-R9 or -NY4Y5, or alkyl substituted by carboxy, -OH, -OR3 or -C(=O)-NY4Y5] and Z1 is CH2; and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  68. A compound of formula (Id) according to claim 34 in which R2 is hydrogen, R3 is optionally substituted phenyl, heteroaryl, or optionally substituted benzyl, A1 is methylene or ethylene, L1 is a
    Figure imgb0321
     group [where R15a represents -N(R8)-C(=O)-R9 or -N(R8)-SO2-R9] and Z1 is CH2; and the corresponding N-oxddes, and their ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  69. A compound according to any one of claims 60, 62, 64, 66, and 68 in which L1 is a group
    Figure imgb0322
  70. A compound according to any one of claims 61, 63, 65 and 67 in which L1 is a group
    Figure imgb0323
  71. A compound according to claim 70 in which R15 represents hydrogen.
  72. A compound according to claim 70 in which R15 represents C1-4alkyl.
  73. A compound according to claim 70 in which R15 represents optionally substituted phenyl.
  74. A compound according to claim 70 in which R15 represents -N(R8)-C(=O)-R9 where R8 is hydrogen or C1-4alkyl and R9 is C1-4alkyl, aryl, heteroaryl, alkyl substituted by alkoxy, alkyl substituted by carboxy or alkyl substituted by -NY4Y5.
  75. A compound according to claim 70 in which R15 represents -N(R8)-C(=O)-OR9 where R8 is hydrogen or C1-4alkyl and R9 is C1-4alkyl or alkyl substituted by aryl.
  76. A compound according to claim 70 in which R15 represents -N(R8)-SO2-R9 where R8 is hydrogen or C1-4alkyl and R9 is C1-4alkyl, aryl, heteroaryl.
  77. A compound according to claim 70 in which R15 represents -NY4Y5 where Y4 and Y5 represent hydrogen.
  78. A compound according to claim 70 in which R15 represents -NY4Y5 where Y4 is hydrogen and Y5 is C1-4alkyl or alkyl substituted by aryl.
  79. A compound according to claim 70 in which R15 represents -NY4Y5 where Y4 and Y5 represent alkyl substituted by aryl.
  80. A compound according to claim 70 in which R15 represents C1-4alkyl substituted by carboxy.
  81. A compound according to claim 70 in which R15 represents C1-4alkyl substituted by -OH.
  82. A compound according to claim 70 in which R15 represents C1-4alkyl substituted by -OR3.
  83. A compound according to claim 70 in which R15 C1-4alkyl substituted by -C(=O)-NY4Y5.
  84. A compound according to claim 70 in which R15 represents -H, -NH2, -NHCH2CH2CH3,
    Figure imgb0324
    Figure imgb0325
    Figure imgb0326
    Figure imgb0327
    Figure imgb0328
    Figure imgb0329
    Figure imgb0330
    Figure imgb0331
    Figure imgb0332
    Figure imgb0333
     (in which R is hydrogen or an aryl group substituent), -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2-OH, -CH2-CO2H or -CH2-OMe.
  85. A compound according to claim 69 in which R15a represents -N(R8)-C(=O)-R9 where R8 is hydrogen or C1-4alkyl and R9 is C1-4alkyl, aryl, heteroaryl, alkyl substituted by alkoxy, alkyl substituted by carboxy or alkyl substituted by -NY4Y5.
  86. A compound according to claim 69 in which R15a represents -N(R8)-C(=O)-R9 where R8 is hydrogen or C1-4alkyl and R9 is selected from 2-chlorophenyl, 5-chloro-2-cyanophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 4-fluoro-2-trifluoromethyl, 2-methyl-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2-nitrophenyl, 3-nitrophenyl and 2-phenoxyphenyl.
  87. A compound according to claim 69 in which R15a represents -N(R8)-C(=O)-R9 where R8 is hydrogen or C1-4alkyl and R9 is selected from quinolin-4-yl, isoquinolin-2-yl, 2,4-pyridin-3-yl, 2,6-dimethyl-4-trifluoromethylpyridin-3-yl, 4-trifluoromethylpyridin3-yl, 2-phenyl-4-methyl-1,2,3-triazol-5-yl, 3,5-dimethylisoxazol-4-yl, 2,7-dimethylpyrazolo-[1,5-a]pyrimidin-6-yl, 2-isopropyl-4-methylthiazol-5-yl and 4-trifluoromethylpyrimidin-5-yl.
  88. A compound according to claim 1 selected from:-
    3-(1-{[3-methoxy-4-(3-[2-methylphenyl]-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-propionic acid;
    3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl)-2,3-dihydro-1H-indol-5-yl)-butyric acid;
    3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-butyric acid;
    3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-pentanedioic acid;
    3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-pentanedioic acid;
    4-[2-carboxy-1-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-ethylcarbamoyl]-butyric acid;
    N-[2-carboxy-1-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-succinamic acid;
    3-(1-{[3-methoxy4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-3-[(5-methyl-isoxazole-3-carbonyl)-aminol-propionic acid;
    2-(2-chloro-6-methyl-benzoylamino)-3-[1-(2,6-dichloro-benzoyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-propionic acid;
    2-(2,6-dichloro-benzaylamino)-3-[1-(2,6-dichloro-benzoyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-propionic acid;
    3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-3-phenylpropionic acid;
    3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-pentanoic acid;
    and the corresponding N-oxide, and its ester prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and ester prodrugs.
  89. A pharmaceutical composition comprising an effective amount of a compound according to claim 1, or a corresponding N-oxide, or an ester prodrug thereof; or a pharmaceutically acceptable salt or solvate of such a compound or its N-oxide or an ester prodrug thereof, in association with a pharmaceutically acceptable carrier or excipient.
  90. A compound according to claim 1, or a corresponding N-oxide, or an ester prodrug thereof; or a pharmaceutically acceptable salt or solvate of such a compound or its N-oxide or an ester prodrug thereof for use in therapy.
  91. A compound according to claim 1, or a corresponding N-oxide, or an ester prodrug thereof; or a pharmaceutically acceptable salt or solvate of such a compound or its N-oxide or an ester prodrug thereof for use in the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of α4β1 mediated cell adhesion.
  92. A composition according to claim 89, for use in the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of α4β1 mediated cell adhesion.
  93. A compound or composition according to claim 1 or 89 respectively for use in the treatment of inflammatory diseases.
  94. A compound or composition according to claim 1 or 89 respectively for use in the treatment of asthma.
EP99943058A 1998-08-26 1999-08-26 Aza-bicycles which modulate the inhibition of cell adhesion Expired - Lifetime EP1114028B1 (en)

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GB9818641 1998-08-26
GBGB9818641.4A GB9818641D0 (en) 1998-08-26 1998-08-26 Chemical compounds
US11000898P 1998-11-25 1998-11-25
US110008P 1998-11-25
PCT/GB1999/002819 WO2000015612A1 (en) 1998-08-26 1999-08-26 Aza-bicycles which modulate the inhibition of cell adhesion

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CA2341677A1 (en) 2000-03-23
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NZ509781A (en) 2003-05-30
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CN1323295A (en) 2001-11-21
TR200100588T2 (en) 2001-08-21
NO20010942D0 (en) 2001-02-23
DE69934238D1 (en) 2007-01-11
DK1114028T3 (en) 2007-04-30
US6608084B1 (en) 2003-08-19
KR20010085630A (en) 2001-09-07
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AU754557B2 (en) 2002-11-21
MXPA01001995A (en) 2004-07-30
NO20010942L (en) 2001-04-19
SK2612001A3 (en) 2001-11-06
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BR9913222A (en) 2001-10-16
HUP0104766A2 (en) 2002-04-29
WO2000015612A1 (en) 2000-03-23

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